Index 653

INDEX

A Agouti-signaling protein (ASIP) A375SM cell lines, PAR-1 promoter activity in, g.8818A/G polymorphism, 356 496, 497 in melanin synthesis, 349 ABCB1 expression in drug resistance, 594–595 and risk, 352, 355–357, 360 ABCB2/ABCB3 (TAP1/TAP2) expression in and pheomelanin synthesis, 88–89 melanoma, 595–596 AIM2, MAGE recognition by, 621 ABCB5 expression in melanoma, 596–597 AJCC (American Joint Committee on Cancer) ABCC subfamily in MDR phenotype, 597–599 guidelines ABC transporters in drug resistance, 593, 594, 599 metastasis, 526 Eo4-N-Acetylgalactos-glycosyltransferase prognosis (GalNac-T) as molecular marker, 553, stage 3 disease, 464–466 559–562 stage 4 disease, 468 Acral lentiginous melanoma (ALM) staging of melanoma, 455–456, 459, 508, 513, described, 201–202, 375, 376, 381 528, 569 growth pattern in, 462 VMO study, 641 Acral melanoma (AM) Akt pathway; see also PI3K described, 202, 203 (Phosphatidylinositol-3 Kinase) pathway progression of, 203–206 Akt-PKB in PI3K signaling, 124–125, 256–258 ACTH. See Adrenocorticotropic hormone (ACTH) in inhibition, 125, 133 D-Actinin, expression of, 383–384 pathway interactions with, 135, 232 Actin in melanogenesis, 383–384 Alkylating agents, inhibition of, 609 Activator protein (AP)-2D O6-Alkylguanine DNA alkyltransferase (MGMT) described, 490 in drug resistance, 578 function of, 490–491 Alleles in melanoma progression, 489, 491–498 of MC1R, 89 to Sp1 ratio, determining, 497 of Mitf, 35–37, 52 transcriptional regulation of, 490 Allelic imbalances (AI) in melanoma diagnosis, Adamts20 gene 462, 554–556, 562–563, 568–569 and melanoblast migration, 6 Amp kinase, regulation of, 277–278 in melanocyte development, 8, 13 Adhesion molecules, expression in melanoma, 5, Analytical epidemiological studies, 315–316 380–383. See also individual molecule by name Anatomical site Adoptive immunotherapy, 643–644 and melanoma incidence, 313, 314, 316, 651–652 Adrenocorticotropic hormone (ACTH) prognosis and, 460, 461, 467, 527 and MC1R, 88 Angiogenesis in pigmentation regulation, 81, 82, 85 described, 534, 535 synthesis of, 88 imaging, 403–404 Aequora fluorescent proteins (AFPs) described, inhibiting, 380, 545–546 399–400 and metastatic phenotypes, 385–388 African descent populations and MMPs, 385 ASIP variants in, 356 and PAR-1, 492 MC1R variants in, 350 regulation of, 506, 536 P protein gene in, 357 as therapy target, 545–546 Age Animal models of melanoma, 303–304, 316–317; and melanoma incidence, 313–314, 316, 321, 322 see also individual animal by common name prognosis and, 460, 461, 467, 469 Antibodies Aggressive melanoma arrays in proteomics profiling, 419–420 in, 533–535 and MIA, 481 molecular studies of, 545 phage display library method, 623 VM in, 541–543 to TA90, 624–625

653 654 Index

Antigens Artifacts in SELDI, 418 gangliosides as, 623 Asian descent populations, ASIP variants in, 356 MAA. See Melanoma-associated antigens (MAA) ASIP. See Agouti-signaling protein (ASIP) as markers, 624 ASIP g.8818A/G polymorphism, 356 Antimetabolite agents, inhibition of, 609 Assay, TA90-IC, 625 Antisense oligonucleotides in chemotherapy, 611 ATF2 and TRAF, 133–134 AP-1 transcription factors, 125, 133 Australian Study described, 444 AP-2D. See Activator protein (AP)-2D Autocrine factors AP-2 C8 cell lines, PAR-1 promoter activity in, in deregulated signaling, 250, 256–257 496, 497 in immune response, 635 APAF-1. See Apoptotic protease-activating factor in MAPK activation, 154 1 (APAF-1) in skin pigmentation, 83–87, 91, 92, 93 APC mutations in melanoma, 120 in VGP, 379–380 Apoptosis Avian models and altered signal pathways, 125, 126, 132, cadherins, 12 217–218 melanoblast migration in, 6 and ATF2, 134 Mitf, 35 C2-ceramide-mediated, 612 Wnt proteins, 173 CDDP-induced, 580, 584, 585 B cell contact and, 383 chemotherapy-induced, 598, 605–606 Bacillus-camillus-guerin (BCG) vaccine, 640 and cyclin D1, 202 Bad protein, inhibition of, 126, 129, 258 inhibitors, targeting, 600 Baltimore Study described, 444–445 INK4a/ARF locus, 268 Barrett’s esophagus, dysplasia in, 516 and keratinocytes, 188 Basal cell carcinomas (BCCs), 443, 445–447 of melanocytes, 92–93, 101, 369–370, 372 Base excision repair (BER) Notch signaling and, 544 DNA damage repaired by, 295 pathways of, 606–608 mechanism, 297, 299–300 promoting, 233, 337, 372–373, 379, 385, in melanoma development, 292 578–579, 611 Basic fibroblast growth factor (bFGF, FGF-2) and the RB-E2F complex, 226, 237 in angiogenesis, 387 regulation of, 506 in Brn2 induction, 255 in RGP, 190–191 in cell signaling, 250, 384 suppression by Rb, 233–234 as hMC mitogen, 86 and telomeres, 205–206 imaging, 404–405 in immune response, 635 TRAIL-induced, 612 in melanocyte growth, 130, 248–249, 379 UV-induced, 108, 110–112, 247, 249, 583, 585 and PAR-1, 492 in VGP, 191–192 in Src kinase activation, 256 Apoptosis deficiency in melanoma, 608–614 synthesis of, 84 Apoptosome Batimastat in angiogenesis inhibition, 385 described, 606, 608 Bax gene in apoptosis modulation, 607, 608, 609 inhibiting, 612 BC chemotherapy response, 571 Apoptotic protease-activating factor 1 (APAF-1) B-cell factor antigens, 622–623 clinical trials of, 613 Bcl2 expression in drug resistance, 598, 606, 607, 612 in apoptosis modulation, 192, 217, 249, 370–372, as molecular marker, 553, 555–556, 563, 568, 570 606–611 Arachidonic acid and keratinocytes, 86 in Brn2-ablated cell lines, 157, 158 ARF (alternative reading frame); see also INK4/ clinical trials of, 613 ARF locus in drug resistance, 578–579, 593 in CDKN2A suppression, 271 in metastatic melanoma, 375 encoding of, 268–269, 279 and Mitf, 42, 57, 62, 254 function of, 187–189 and UVR-induced apoptosis, 93 and UVR damage, 280 BCL-XL Argyrophilic nucleolar organizer regions clinical trials of, 613 (AgNORs) described, 378 in drug resistance, 579, 609, 611 Array-based proteomics profiling, 419–420 bFGF. See Basic fibroblast growth factor (bFGF, Array genomic hybridization described, 375 FGF-2) Index 655 bHLHLZ (basic helix–loop–helix– zipper) C transcription factors C219 and P-gp expression, 595 in cancer, 61 Cadherin 1 (CDH1) gene in melanoma Mitf. See Mitf (microphthalmia associated susceptibility, 338 transcription factor) Cadherin expression Bioinformatics and proteomics profiling, 422 expression in melanoblasts, 5, 12 Bioluminescence imaging (BLI) described, 400–403 and Frizzled receptors, 173–176 Biomarkers gene ablation, consequences of, 173 APAF-1, 553, 555–556, 563, 568, 570 in melanoblast migration, 12 CDKN2A, 553, 555 melanocytes, shift by, 176–177, 250–251 DAPK, 553, 555, 556, 568 and RTKs, 169, 177–178 detection in blood, 564–568 in signal transduction/cell adhesion, 170–173 developing, 552–554, 597 E-Cadherin expression GalNac-T as, 553, 559–562 and AP-2D, 491 identifying, 414–415, 435–438, 504–505, 509 in breast cancer, 59 LOH, 562, 563 function of, 170–173 MAGE-3, 559–562, 565–567 gene ablation, consequences of, 173 MART1, 559–562, 570 in melanoblasts, 12, 18, 59, 158 MCAM/MUC-18, 553, 555, 565–567 regulation of, 169–170, 250–251, 257, 258, melanotransferrin (p97) as, 553, 565–567 276, 379 MIA as, 485 N-Cadherin expression p16 protein, 553, 555 expression in melanoblasts, 12, 158, 172, 173 PAX3 gene, 553, 555, 559–562 function of, 170 in prognosis, 462–464, 467–468, 551 gene ablation, consequences of, 173 serum, 485 regulation/function of, 171, 250–251, 257 TIMP3, 553, 555 P-Cadherin expression tyrosinase, 553, 558, 559, 560, 570 in the epidermis, 170 uMAG-A, 553, 565–567 expression in melanoblasts, 12 gene ablation, consequences of, 173 Blastocyst formation via sno, 212 regulation/function of, 171 Blood, marker detection in, 564–568 VE-Cadherin expression Blue nevi in angiogenesis/vasculogenesis, 536, 538, 539, described, 198, 199 540, 545–546 VEGF in, 386 in melanoma cells, 170 BMPs2 and 4 gene in melanocyte development, 8 regulation/function of, 171 Bone marrow metastasis, 572–573 Calcitonin gene-related peptide (CGRP) and Bone morphogenetic proteins (BMPs) in melano- melanocytes, 84 blast induction, 14 Calmodulin in array-based proteomics, 419 Bottom-up (shotgun) proteomics profiling, 420–422 cAMP BRCA2 mutations, 93, 338 and ASIP, 355 Breslow depth. See Thickness of tumor and cell cycle regulation, 370 prognosis induction and AP-2_, 490 Brn2 gene in MAPK activation, 274 ablation, expression profiling of, 155–159 in MC1R regulation, 272, 353 described, 150, 162 in Mek/Erk activation, 253, 254 DNA binding in, 150–154 in Mitf regulation, 55, 75, 129, 248, 257 expression of in melanoma, 38, 122, 129, 252 in UVR response, 91 functions of, 159–161 Camptothecin, chemosensitivity to, 612 in Mek/Erk activation, 254–255 Cancer, Mitf in, 61–62 in melanocyte differentiation, 151–153 Cancer stem cells, 545 in melanoma, 153–155 Cancer/testis (CT) antigens described, 622 in Mitf regulation, 38, 44 Canvaxin in immune response, 625, 640 target promoters, identifying, 161–162 Carboplatin BRN3b (POU4F2) in cell regulation, 154 resistance to, 580 ETRCP, inhibition of, 133 response rate as single agent, 592 Burkitt’s lymphoma, 61 Carmustine, response rate as single agent, 592 656 Index

Caspases in apoptosis, 606–608, 611–612, 614 Central nervous system (CNS) metastases, 571 E-Catenin; see also Wnt/E-catenin-signaling Ceramide in apoptosis, 612 pathway CFTR-MRP. See ABCC subfamily in MDR and Brn2 expression, 154–155 phenotype in cell signaling, 170, 172, 174, 211, 232 CGRP. See Calcitonin gene-related peptide (CGRP) and Dct, 77 Chemokines, 437, 635 gene ablation, consequences of, 173 Chemotherapy in melanocyte development, 11–12, 56, 120–122 and 2D-PAGE, 414 mutations in, 192 about chemotherapy, 578–579, 591, 592, phosphorylation of, 120, 174 598–599, 605–606 and SKI, 217–218 in CNS metastases, 571 and Sox10, 76 resistance to targets, nuclear, 175 ABCB1 expression in, 594–595 and Wnt5a, 123 ABC transporters in, 593, 594, 599 Cationic liposome–DNA complexes (CLDCs) in CDDP, 579–581, 584 gene/pathway identification, 504–505 and Dct, 577, 580–581, 583, 585–586 Catnb gene in melanocyte development, 7 DNA damage/repair in, 578, 583, 584, 593, CBP/p300 in Mitf regulation, 39 598, 606 CCL21/SLC (cc-ligand-21/secondary lymphoid tissue efflux mechanisms in, 578, 583, 591–593, 599 chemokine) in lymph node drainage, 437 Fas gene in, 598, 606, 608–609, 612 CCND1 gene in cancer, 120 gene expression and, 593–594 CCR7 in lymph node drainage, 437 MDR. See Multidrug resistance (MDR) CD31 in SLN metastasis, 437 mutations in, 593–594 NF- B signaling pathway, 585, 598, 609 CD36 expression in cell migration, 381 N overcoming, 134, 283, 545, 585–586, 592 CD40 expression in melanoma, 388 p53 gene in, 578, 598, 608 CD44 expression P-gp in, 592–595, 599 described, 382 survivin, 579, 600, 608 and prognosis, 463 TNF-D, 585, 598, 609 CD63 in Brn2-ablated cell lines, 157, 158 Chick models CD95. See Fas gene Adamts20 gene, 13 CDDP resistance locus 1" (CRL-1), location of, 580 BMPs, 14 Cdh gene in melanocyte development, 7 Efnb, 13 CDK. See Cyclin-dependent kinase (CDK) activity Foxd3, 16 Cdk2. See Cyclin-dependent kinase 2 (CDK2) neural cell migration, 4–6, 11, 13 CDK3. See Cyclin-dependent kinase 3 (CDK3) Snail family genes, 18 CDK4. See Cyclin-dependent kinase-4 (CDK4) Sox10, 72 CDK6. See Cyclin-dependent kinase-6 (CDK6) Chondrosarcomas, MIA in, 475 CDK kinase inhibitors (CKI), 228 Choroidal melanoma, P-gp expression in, 595 INK4A CDKN2A; see also p16 protein Chroma defined, 335 deficiencies, effects of, 188–189 Chromatin modification, 224, 225 described, 187–188, 303, 366–369 aberrations. See also DNA in melanoma risk, 231, 249, 318, 337, 443, 556 in blood, 568 as molecular marker, 553, 555 dysplastic nevus syndrome, 366, 368–370, 555 suppression of, 270 in melanoma, 120, 199, 202–206, 265, CDKN2B gene 375–376, 555 in melanoma suppression, 269 melanoma vs nevi, 199, 200, 205 mutations in melanoma, 337, 338 SKI, 215 CDKNA/B and DNA methylation, 226 in Spitz nevi, 201 CD-RAP (cartilage-derived retinoic acid-sensitive Chx10 mutations and Mitf expression, 38, 42 protein). See Melanoma inhibitory activity Cisplatin (MIA) in chemotherapy regimens, 598–599 CDT regimen in chemotherapy, 599 resistance to, 597, 609, 612, 614 CEACAM1 in prognosis, 463–464 response rate as single agent, 592 Cell contact and apoptosis, 383 Clark classification of pigmented lesions Cell cycle accuracy of, 430 progression and Rb/E2F, 228–229 described, 184–185, 189, 459, 514 proliferative activity, markers of, 377–378 genetic basis for, 189–191 regulation of, 367, 506 prognosis and gender, 527 Index 657

Class-Y polymerase genes in DNA repair, 301, 302 and Mitf, 42 Clonal autonomy in melanoma, 379, 387 and Rb/E2F, 226, 230 CMM4 in melanoma susceptibility, 187 in TGF-E repression, 216 Cockayne syndrome (CS), DNA defects in, 298, 299 Cyclin-dependent kinase 3 (CDK3), 226 Collagens Cyclin-dependent kinase-4 (CDK4) in angiogenesis/vasculogenesis, 536 in cell cycle regulation, 367–370 in melanocyte development, 7, 13, 381–382 described, 303 and MMPs, 384, 385 inhibition of, 318, 337 Color of saturation defined, 335 in melanoma susceptibility, 187, 231, 266, Common acquired nevi. See Nevi, common 268–270, 337–339 acquired in Rb hyperphosphorylation, 268 Comparative genomic hybridization (CGH) regulation of, 43–44, 130, 226 described, 375 Cyclin-dependent kinase-6 (CDK6) Complexion in melanoma risk, 348, 360 in cell cycle regulation, 367 Computed tomography (CT), 552 inhibition of, 318, 337 Confocal microscopy described, 400 in melanoma development, 268, 269 Congenital nevi described, 201 and Rb/E2F, 226, 231 Cortactin and Src kinases, 256, 257 Cyclin-dependent kinase (CDK) activity Covalent modification, changes in and melanoma activation in melanoma, 231, 238 progression, 415 phosphorylation sites, 227 Cowden syndrome, 318 protein pocket inactivation, 229 CREB (cAMP responsive element binding and Rb function, 223, 226, 236, 268 protein) regulation of, 228, 233 and Dct, 77 Cyclin-E in Rb transcription, 226–228, 236 in MCAM/MUC18 regulation, 382–383 Cyclophosphamide, DNA damage by, 578 in Mitf regulation, 37–38, 54, 55, 75, 76 Cytochrome-c in apoptosis modulation, 606, 607, phosphorylation of, 37–38, 93, 272 609, 614 and Rb/E2F, 232 Cytokines Crisis defined, 205, 206 C-terminal binding protein (CtBP) and MIA in apoptosis, 612 inhibition, 483–485 in immune response, 635, 636 CTNNB1 mutations in melanoma, 120 in immunotherapy, 636–639 Cutaneous malignant melanoma (CMM) in MAA modulation, 624 development of, 311–312, 322–323 in melanocyte response, 379–380 epidemiological studies of, 312–316, 319–320 in regression, 634 gene expression in, 533–534, 537 in skin inflammation, 84–85, 92 histopathological studies, 316 Cytoskeleton, components of, 383–384 immune response to, 634 D MC1R variants in, 354 Mediterranean populations Dacarbazine prevalence of, 330–331 in chemotherapy regimens, 598–599, 609 risk factors for melanoma, 331–340 DNA damage by, 578 study subjects/methods, 330–331 and IFND2b, 637 molecular studies of, 317, 541–543 response rate as single agent, 592 prevalence, 329–330 Dct. See Dopachrome-tautomerase (Dct) Cutaneous pigmentation. See Pigmentation, Death-associated protein kinase (DAPK) cutaneous hypermethylation in, 571 CXCR2, imaging, 405 as molecular marker, 553, 555, 556, 568 CXCR4, expression of, 385 Death-inducing signaling complex (DISC) Cyclin-A, regulation of, 134, 229, 230 described, 606 Cyclin D1 Death receptor family described, 606 in cell cycle regulation, 367–368 Defined antigen vaccines, 642 function of, 226 Dendritic cells (DCs), imaging, 402 inhibiting, 303 Desmocollin, regulation/function of, 170, 171 in melanoma, 202, 204, 230–233, 376 Desmoglein, regulation/function of, 170, 171, 276 in Spitz nevi, 199, 377 Desmoplastic neurotropic melanoma described, 462 Cyclin-dependent kinase 2 (CDK2) Development of melanocytes. See Melanocytes, and Erk, 129 development of 658 Index

Development of melanoma damage about melanoma development, 291, 311–312, classification of, 293 322–323, 347, 521–527 in drug resistance, 583, 584, 593, 606 divergent pathway hypothesis, 320–322 recognition of, 296–298 and dysplasia, 516 replication of, 300–301 genetic basis of, 347–349, 442–443 via therapy, 578–579 NER, 292, 444–449 markers INK4A p16 –cyclin D–CDK4/6–RB pathway, about, 553–557, 562–564, 570–571 268–270, 337 detection in blood, 567–569 p53 gene mutations methylation of, 226, 598 apoptosis-inducing, 337, 370–372 photoproducts and p19ARF, 236 damage to, 300–301, 303 in senescence, 185–188, 191–193 and mutation, 301–302 UV-specific, 318, 444 repair; see also DNA repair capacity (DRC) suppressing, 269, 623–626 UVR. See UV radiation BER. See Base excision repair (BER) and UVR class-Y polymerase genes in, 301, 302 incidence, rise in, 265, 266, 291, 369 deficiencies and melanoma, 299 molecular basis of, 279–280, 291, 292, in drug resistance, 578, 598 442–444 enzyme defects in, 300 and p16INK4A, 270, 303 mechanisms of, 293–302, 340 DHICA in drug resistance, 584, 585 and melanoma risk, 333–334, 348, 441 Diagnosis of melanoma and Mitf, 93 allelic imbalances (AI) in, 554–556 NER. See Nucleotide excision repair (NER) features of melanoma, 521–522, 605 p53 gene in, 296, 298, 299, 302 and MAAs, 624 TCR. See Transcription-coupled repair (TCR) primary tumor, 554–557 of UVR-induced damage, 111, 273, 291, using SELDI, 419 293–295 VGP, 525 synthesis, preventing, 578 cis-Diamminedichloroplatinum(II) (CDDP) DNA methyltransferase (DNMT) and Rb tran- DNA damage by, 578 scription, 225, 226 in drug resistance, 579–581, 584 DNA microarrays in proteomics profiling, 419 Dickkopf 1 and melanocyte growth, 104 DNA repair capacity (DRC) Diffuse optical tomography (DOT) described, 401 in dysplastic nevi, 444, 447 Dihydrofolate reductase (DHFR) promoter, and melanoma risk, 441, 443, 444–449 activation of, 224, 230, 236 DOPA. See 3,4-Dihydroxyphenylalanine (DOPA) 3,4-Dihydroxyphenylalanine (DOPA) in melanin Dopachrome-tautomerase (Dct) synthesis, 102, 152 and ASIP, 355 Disheveled (Dsh) protein in Brn2-ablated cell lines, 155, 157, 158 and E-catenin degradation, 174 DNA binding in, 75 in GSK-3 inhibition, 120, 121 Dithiothreitol in N-Oct-3 complex formation, 151 expression of, 5, 19, 38, 57–58, 76, 253, 582–583 Divergent pathway hypothesis described, 320–322 gene locus/function, 581 DNA immunotherapy, 583–584 adducts in melanin production, 102, 105–106, 349 producing, 295, 597 and Mitf, 76 repair of, 296 as molecular marker, 553, 559, 560, 570 binding mutations in, 581–582 in Brn2, 150–154 and P protein expression, 359 dopachrome-tautomerase (Dct), 75 resistance to chemotherapy/radiotherapy, 577, 580–581, E2F, 229 583, 585–586 by Mitf, 37, 39, 41, 43, 52, 57 mechanisms of, 584 PAR-1, 492–493, 497 and Sox10, 76 repression by SKI, 215 transcriptional regulation of, 272 SH3 domains, 478, 480, 481 Dormancy in melanoma, 430; see also Regression by Sox proteins, 72, 74, 75, 76 in melanoma by TFE3, 61 Dorsal-lateral pathway copy number changes in melanoma, 200, 203, Kit expression in, 15–16 204, 375–376 in melanoblast migration, 28 Index 659

Doxorubicin, chemosensitivity to, 612 EphA2 (Erythropoietin-producing hepatocellular Doxycycline and Ras mutations, 281 carcinoma-A2) in angiogenesis Drug detoxification proteins, identifying, 414 vasculogenesis, 536, 538, 539, 540, 545–546 Drug resistance. See Chemotherapy, resistance EphB. See Ephrin-B (EphB) Dysplasia defined, 516, 520 Ephrin-B (EphB) Dysplastic (atypical) nevi. See Nevi, dysplastic expression in melanoblasts, 5 Dysplastic nevus syndrome in melanoblast migration, 13 chromosome aberrations in, 366, 368–370, 555 described, 516 in melanocyte development, 8, 13 familial, 368, 370 Epidemiological studies, 312–316, 319–320, 446–448 imaging, 406 Epidemiology of melanoma, 442 as risk factor, 190, 441 Epidermal melanin unit described, 82, 169 Epidermis; see also Pigmentation, cutaneous E DNA damage to, UV induced, 108–111, 273 E1a gene in cancer, 375 melanin distribution in, 107 E2F family proteins melanocytes in, 4, 104, 105 in cell cycle regulation, 367, 369 ulceration in, 458 clinical applications, 237–238 Epigenetic alterations in melanoma, 556, 564, in melanocyte development, 228–229 570–571 structural domains of, 227 Epstein-Barr Virus (EBV) in gene delivery transcription by, 224–226, 268 therapy, 505, 506 Eastern Cooperative Oncology Group (ECOG) 1684 study, 637, 638, 641 ERCC1 repair enzyme in drug resistance, 578 ECM proteins. See Extracellular matrix (ECM) ERK gene; see also MEK-ERK pathway proteins activation of, 252, 256, 585 ECOG (Eastern Cooperative Oncology Group) in apoptosis inhibition, 125 1684 study, 637, 638, 641 inhibition of, 128–129 Edn3 (Endothelin 3) gene in melanoma pathogenesis, 127–129, 132, 276 in melanocyte development, 8, 13, 14, 15, 41 pathway interactions with, 135, 251, 275 mutations in, 14 Erythema as risk factor, 442 Efflux mechanisms in drug resistance, 578, 583, Erythropoietin-producing hepatocellular carci- 591–593, 599 noma-A2 (EphA2) in angiogenesis Efnb gene, 8, 13 vasculogenesis, 536, 538, 539, 540, 545–546 Eicosanoids in skin inflammation, 84–86 Escherichia coli, MS profile of, 412 E-Endorphin in hMC regulation, 89 Esterase activity, extracellular, 417 Endostatin effects, 546 ET-1. See Endothelin-1 (ET-1) Endothelial cells, 544, 545 Endothelin-1 (ET-1) Eumelanin in apoptosis inhibition, 188 DNA damage via, 295 and Brn2 expression, 158 and photoprotection, 333, 348 in pigmentation regulation, 81, 82, 87–89, in skin color regulation, 82, 83, 581 248–249 synthesis of, 88, 273, 355, 582 and UVR, 90, 92 European descent populations Endothelin-3 (EDN3) in Brn2 expression, 154, 158 ASIP variants in, 356 Endothelin receptor B (Ednrb) pathway melanoma prevalence in, 651 binding in, 87 P protein gene in, 357 in Brn2-ablated cell lines, 157, 159 Extracellular matrix (ECM) proteins in melanocyte development, 8, 14, 41 binding receptors in, 48, 382, 480, 481 mutations in, 14–15, 53 and cell survival, 249, 388 in neural crest cell proliferation, 6 and cellular transport, 129 in skin pigmentation, 248 expression in melanoblasts, 5, 13 Environment; see also Sunlight exposure as risk factor; UV radiation and integrins, 380 and genetics, 279–280 and vascular mimicry, 534, 538–539 melanocyte response to, 103–107, 202–203 and Wnt signaling, 119 as risk factor, 279–280, 369 Extravascular migratory metastasis described, 388 and study data, 314–315, 321 Eyes Enzymes color and melanoma risk, 354, 356–358, 447 defects in DNA repair, 300 melanocytes in, 29, 30 in immune response, 635 Mitf in, 36, 42, 59 in metastasis, 385, 417 samples, SELDI analysis of, 418 660 Index

F Forskolin and MITF, 55 Fos expression and AP-1, 133 Familial melanoma. See Hereditary (familial) Foxd3 gene in melanocyte development, 9, 16 melanoma Freckles Farnesyl thiosalicylic acid and melanoma defined, 331 progression, 609, 610 and melanoma risk, 354, 360, 442, 519 Fas-associated protein with death domain Frizzled (FZD) receptors (FADD) in apoptosis, 606, 611 in Mitf regulation, 56 Fas gene in Wnt signaling, 120, 121, 123, 173–176 in drug resistance, 598, 606, 608–609, 612 Fyn kinase in immune response, 635 activation of, 257 in melanoma development, 371–373 function of, 256 regulation of, 374, 385 Fetal antigens in MAA reactivity, 622 G FGF. See Fibroblast growth factor (FGF) GADD45, induction of, 299 FGF-2. See Basic fibroblast growth factor (bFGF, E-Galactosidase in benign nevi, 190 FGF-2) GalNac-T (Eo4-N -acetylgalactos- FHL-2 protein in E-catenin activation, 211, 217 glycosyltransferase) as molecular marker, Fibroblast growth factor (FGF) 553, 559–562 activation of, 233 Gangliosides as antigens, 623, 637 in Brn2 expression, 154 Gel quality and quantification and CDK activity, 232 in 2D-PAGE, 412–415 in Erk inhibition, 128 in MudPIT, 422 Fibroblasts Gender and prognosis, 460, 461, 469, 526–527 and actin, 383 Gene delivery in gene identification, 504–505, and hMC proliferation, 84 579–580 in human pigmentation, 89–90, 92, 104 Gene expression life span of, 205–206 in aggressive melanoma, 533–535, 545–546 Rb promoters in, 229 in drug resistance, 593–594 senescence in, 185, 186, 187, 217 in melanocytes described by gene, 7–10, 156 and UV damage, 442, 444 identifying, 6, 29, 31, 347–350 Fibronectin Mitf, 56–59 in angiogenesis/vasculogenesis, 536 of micrometastasis in SLNs, 436 in melanocyte development, 7, 13, 382 molecular studies of, 317, 415–417 Field cells, 203–205 pigmentation, interactions, 359–360 FISH in identification of chromosome aberrations, 205 and provirus, 579 Fish models; see also Zebrafish models RB/E2F, control of, 225 advantages of, 303 silencing by Rb, 226 Mek inhibition, 253 Gene identification, gene delivery in, 504–505, PI3K, 258 579–580 Src kinases, 256 Genotype assays, DRC, 448 Wnt proteins, 173 GGR. See Global genome repair (GGR) Xmrk expression in, 250, 253 Glioblastoma FKBP12, regulation of, 507 gene inactivation in, 271, 280 FKBPr38, regulation of, 507 vaccination for, 584 FKHR in Pax3 activation, 130 Glioma, malignant and Dct expression, 584 FLIPs described, 611, 612 Global genome repair (GGR) Fluorescence microscopy described, 400, 401 described, 294, 296 Fluorescence molecular tomography described, 401 mechanism, 298–299 Fluorescence resonance energy transfer (FRET) Glucocorticoid-based therapy as protective, 332 described, 403 Glutathione-S-transferase (GST) deficiency and Fluorescent dyes in proteomics profiling, 412, 414 melanoma risk, 443–444 Fluorescent probes described, 399–400 Glutathione-S-transferase P1 (GSTP1), 553, 555, 568 5-Fluorouracil (5-FU), mechanism of action, 578 Glycine receptor, imaging, 402 c-FMS in Mitf regulation, 38 Glycogen synthetase kinase (GSK)-3 Focal adhesion kinase (FAK) in VM, 539, 540 in E-catenin phosphorylation, 120, 121 Forkhead family in Pax3 activation, 130 in pathway interactions, 135, 232, 258 Index 661

GM-CSF. See Granulocyte macrophage colony- Hepatoma-derived growth factor (HDGF), 415 stimulating factor (GM-CSF) Hereditary (familial) melanoma GMK vaccine, 637 described, 266, 269 Goat models of melanoma, 317 diagnosis of, 302–303 GP100 protein genetic basis of, 266–273, 368, 442–443 in bone marrow metastases, 572 Mediterranean populations, 336–340 expression of, 583 Heregulin, function of, 250 Herpes thymidine kinase gene, expressing, 238 MAGE recognition by, 621 Heterochromatin protein 1 and Rb transcription, 225 in melanin production, 102, 105 HETEs (Hydroxyeicosatetraenoic acids), 86 GPCR signaling, 274, 276 HGF. See Hepatocyte growth factor (HGF) GPM6B gene in Brn2-ablated cell lines, 157 HGF–MET–PAX3 pathway, 129–131 G protein and PAR-1, 492 Hgf transgenic model, 280 Granulocyte macrophage colony-stimulating High-dose interferon therapy (HDI), 637–639 factor (GM-CSF) High-mobility group (HMG) transcription factor in immune response, 635, 643 family in melanoma proliferation, 379, 380 LEF-1/TCF. See LEF-1/TCF transcription Griscelli’s syndrome, 91 factor Growth factors/receptors in melanocyte develop- MATF. See MATF (melanoma-associated ment, 8, 13–16; see also individual factor transcription factor) described by name SOX10. See SOX10 gene Growth pattern, stage I/II tumors in prognosis, 462 Hirschsprung disease and ETBR, 87 GSK-3. See Glycogen synthetase kinase (GSK)-3 neural crest cell defects and, 19 GST. See Glutathione-S-transferase (GST) and Sox10, 73 Guanosine triphosphatase (GTPase) family, 126 Histology in melanoma diagnosis, 520–521 H Histone deacetylase (HDAC) function of, 215, 216 Hair color in melanoma risk, 348, 353–354, 356, and Rb transcription, 224, 225, 236–237 447; see also RHC phenotype Histopathological studies, 316 Hair follicles HLA-DR (human leukocyte antigen-D related), 635 BMPs in, 14 HMB/pmel17/silver regulation by Mitf, 61 melanocytes in, 4, 13, 234 hMC. See Human melanocytes (hMC) Hair follicles, melanoblast migration in, 6 HOX genes in pigmentation, 103–104 Hamster models hTERT. See Human telomerase reverse MIA, 481 transcriptase (hTERT) HDAC. See Histone deacetylase (HDAC) Hue angle defined, 334 Hue defined, 335 HDGF. See Hepatoma-derived growth factor Human melanocytes (hMC) (HDGF) and bFGF, 86 Hearing issues HETEs and, 86 and melanocytes, 29, 31 leukotrienes and, 86 Sox10 and, 73 MC1R, 88–89 Heat shock protein 70 (Hsp70) expression in prostaglandins, 85–86 melanoma, 612 regulation of, 84, 89 Heat shock protein 90 (Hsp90) expression in thromboxanes, 85–86 melanoma, 374, 612 Human models Heat shock resistance and Dct expression, 585 ARFs, 188 Hepatocyte growth factor (HGF) B-Raf, 127 and AP-2D, 491 CDKN2A, 188–189 in cell signaling, 250, 256–257, 274 cell senescence, 185–187 in Erk inhibition, 128 Dct-mediated drug resistance, 580–581 regulation of, 130 melanoblast migration, 6 in Src kinase activation, 256 Mitf mutations, 52 Hepatocyte growth factor (HGF)/scatter factor skin color, 82–83 (SF) Sox10, 72–73 in ATF2 regulation, 134, 135 tyrosinase, 57 in melanoma, 233 Human telomerase reverse transcriptase (hTERT) in normal melanocytes, 130 in human cells, 185 in signal pathway activation, 274, 276–277 in melanoma, 202 synthesis of, 84, 85, 86 in senescence, 187, 188, 190–192 662 Index

Hyaluronate binding, 382 rise in, 265, 266, 291, 369 Hydroxyeicosatetraenoic acids (HETEs), 86 in US, 366, 430, 442, 552, 592 Hypermethylation in melanoma progression, 556, in women, 313, 330, 447 564, 570–571 Incubator hypothesis vs marker hypothesis, 433–436 Hypersensitivity response, modulating, 625, 634, 640 Indoleamine 2,3-dioxygenase in immune response, 635 I Inhibitor of cyclin-dependent kinase- 4 (INK4)/ IAPs. See Inhibitors of apoptosis (IAPs) alternative reading frame (ARF). See ICAM-1 expression INK4/ARF locus and AP-2D, 490, 491 Inhibitors of apoptosis (IAPs) and VEGF, 386 in caspase inhibition, 611 ICAT protein described, 606–608 INK4A. See p16INK4A protein in melanoma pathogenesis, 120, 121 INK4/ARF locus in melanoma development, 226, in Wnt pathway regulation, 122 266, 268–269, 271, 273 Identification INK4 family members, CKI described, 228 of drug detoxification proteins, 414 Inositol-3,4,5-triphosphate (IP3) kinase pathway, 93 gene delivery in, 504–505, 579–580 Insulin growth factor-1 (IGF-1) gene expression in melanocytes, 6, 29, 31, and E-catenin, 174, 176 347–350 in Brn2 expression, 159 of markers, 414–415, 435–438, 504–505, 509 in melanocyte growth, 379 mobility changes, 413 Insulin growth factor-1 (IGF-1R) receptor proteins. See Protein identification activation of, 233 IEF. See Isoelectric focusing (IEF) inhibition of, 235–236 IKK and TRAF2, 132–133 D3E1 Integrin, binding in, 380 Imatinib mesylate (STI571) in MDR modulation, 600 D3E3 Integrin, binding in, 380 Immune response; see also B-cell factor antigens; D4E1 Integrin, binding in, 482 T-cells D4E5 Integrin, binding in, 482 Canvaxin in, 625 D6E1 Integrin, binding in, 380 and disease progression, 619–620 Integrin-linked kinase (ILK) described, 233 to gene delivery therapy, 505, 584 Integrins to MAAs, 619–620, 624, 635, 636 D, binding in, 380, 481, 482 natural described, 634–636 DQE3, 380–381, 492 TA90, 624–626 D antibodies and MIA, 481 Immunoglobulin (Ig)-G and TA90, 624, 625 E-integrins Immunoglobulin (Ig)-M and TA90, 624, 625 and prognosis, 463 Immunotherapy regulation of, 379–381, 482, 507 about immunotherapy, 636–644 in RGP vs VGP, 525 in collagen binding, 382 active described, 633 and ECM molecules, 482 adoptive, 643–644 in melanocyte development, 7, 13, 129, 233, cytokines in, 636–639 249–251, 257, 380–381 and Dct, 583–584 osteopontin and, 255 Dct and, 583–584 and SCF, 87 development of, 633–634 DQE3 Integrins IFN-D2b in, 636–639, 641 and angiogenesis, 380–381 IL-2 in, 638–639, 643 expression in , 381 MAAs in, 620–622, 626 and PAR-1, 492 passive described, 633–634 Interferon-D L-Selectin in, 644 TILs in, 643–644 in chemotherapy regimens, 598–599, 609 tyrosinase in, 583 protein response to, 414 vaccines in, 639–640 response rate as single agent, 592 Incidence of melanoma Interferon-D2b in immunotherapy, 636–639, 641 by age, 313–314, 316, 321, 322 Interferon-J by anatomical site, 313, 314, 316, 651–652 and Fas expression, 373 in men, 313, 330, 447 in regression, 634 by occupation, 314–315 Intergroup study E1690, 637 and radiotherapy, 270 Interleukin-1 (IL-1) Index 663

in Brn2 expression, 159 K in immune response, 635 Kaposi’s sarcoma, 545 in skin inflammation, 84–85, 92 Keratinocytes and tyrosinase activity, 378 in apoptosis inhibition, 188 in VGP melanoma, 379 and arachidonic acid, 86 Interleukin-2 (IL-2) and bFGF, 86 in chemotherapy regimens, 599, 609 described, 81, 169, 522 in immunotherapy, 638–639, 643 in human pigmentation, 89–90, 103, 104, 248 in regression, 634, 636 and melanocytes, 82, 83, 84, 91, 249, 267, response rate as single agent, 592 378, 379 Interleukin-4 (IL-4) receptor in immune response, p53 mutations in, 372 635, 643 renewal capacity of, 82 Interleukin-6 (IL-6) UV response, 107, 111 in cell signaling, 250 Keratins in metastasis, 383 in immune response, 635 Ki-67 antibody and melanocyte proliferation, 378–380 in cell proliferation, 377, 381 regulation of, 134, 372 in RGP vs VGP, 525 in skin inflammation, 84–85 c-Kit gene and AP-2 , 489, 491 Interleukin-8 (IL-8) D and SCF, 87 in Brn2 expression, 159 Kitl expression in cell signaling, 250, 378, 379 function of, 29 in Erk inhibition, 128 in melanocytes, 9, 15, 32, 41 and PAR-1, 492 in UV-induced melanogenesis, 248 Interleukin-10 (IL-10) Kit signal transduction pathway in cell signaling, 250 expression of, 15–16, 29, 250 in immune response, 635 in melanocyte specification, 5–6, 9, 13, 14, 32, 41 Interleukin-24 (IL-24) in Brn2 expression, 159 and Mitf, 38, 253–254 Invasion of tumor cells mutations in, 15, 29, 87 defined, 522 Korean descent populations, ASIP variants in, 356 and MIA, 481 and PAR-1, 492 L in prognosis, 459 L65P mutant in melanoma susceptibility, 338, 339 regulation of, 506–507 Lactic dehydrogenase (LDH) in prognosis, 469 and vascularity, 508–510 Laminin Ion cyclotron resonance (ICR) instruments in angiogenesis/vasculogenesis, 536, 538, 539, described, 410 541, 543, 545 Ion trap instruments, 3D described, 410 expression in melanoma, 388, 481, 482 Isoelectric focusing (IEF) in proteomics profiling, Laminin in melanocyte development, 7, 13 411–412 Lectin gene in melanocyte development, 7 Italy Lef1 gene expression CMM in, 330–331 and Dct, 77 melanoma studies in, 446–447, 449 in melanocyte development, 7 and Mitf, 19, 37, 40, 59, 75, 76 J LEF-1/TCF transcription factor JAK proteins and E-catenin, 174, 217 in apoptosis inhibition, 126, 131–132 in gene transcription, 120, 121, 122 deregulation of, 259 in melanocyte development, 7 and IL-2, 638 in Mitf regulation, 54, 56 in melanocyte survival, 129 and Rb/E2F, 232 Jamaican descent, MC1R variants in, 350 Lentigo maligna melanoma (LMM) JNK activation bFGF in, 387 by cadherins, 174 described, 201–202, 205, 376 by TRAF proteins, 132 development of, 312, 313, 321 Jun expression growth pattern in, 462 and AP-1, 133 Lesions, pigmented. See Nevi and ATF2, 134 Leukotrienes, hMC response to, 86 664 Index

Level of invasion in prognosis, 459 MAPK pathway LIM protein family domains described, 217 activation of, 121, 154, 248, 585 Lipase activity, extracellular, 417 and B-Raf, 125–127 Lipid peroxidation and UVR, 295 and Brn2 expression, 122 LKB1 described, 277–278 in melanoma pathogenesis, 201, 274–276, 319 Loss of heterozygosity (LOH) in Mitf regulation, 38–39 in diagnosis, 554–556, 568–570 mutations in, 198, 199 as marker, 562, 563 and PAR-1, 492 prevalence in melanoma, 277, 278 pathway interactions with, 135, 232–233 Lung involvement in melanoma, 431 and Spitz nevi, 376–377 Lymphatic endothelial hyaluronan receptor-1 as in TRAF regulation, 125 marker, 509 Marker hypothesis vs incubator hypothesis, 433–436 Lymphatic endothelial marker (LYVE-1) in SLN Markers metastasis, 437 antigens as, 624 Lymphatic mapping, benefits of, 557 APAF-1, 553, 555–556, 563, 568, 570 Lymph node dissection, benefits of, 557 CDKN2A, 553, 555 Lymph nodes/system DAPK, 553, 555, 556, 568 in cancer staging, 456 detection in blood, 564–568 development in melanoma, 386–387, 509 developing, 552–554, 597 DNA markers in, 563 DNA. See DNA, markers and metastasis, 430, 431, 437, 504, 552, 652 expression of, 559 in prognosis, 557 GalNac-T as, 553, 559–562 and survival rates, 436, 552 identifying, 414–415, 435–438, 504–505, 509 in targeted therapy, 545, 644 Lymphocytes LOH, 562, 563 imaging, 402 MAGE-3, 559–562, 565–567 infiltration of and prognosis, 461–462 MART1, 559–562, 570 Melan-A/MART-1, 624 MCAM/MUC-18, 553, 555, 565–567 response, RGP vs VGP, 525, 526 melanotransferrin (p97) as, 553, 565–567 tumor cell lysis by, 638 MGMT, 553, 555, 556, 568 and UV damage, 442, 444 MIA as, 485 Lymphokine-activated killer cells (LAK), 638, 639 mRNA. See mRNA markers LYVE-1 in aggressive melanoma, 543 p16 protein, 553, 555 PAX3 gene, 553, 555, 559–562 M in prognosis, 462–464, 467–468, 551 M0 senescence described, 186–187, 190 serum, 485 M1 senescence described, 185, 188 TIMP3, 553, 555 MAA. See Melanoma-associated antigens (MAA) tyrosinase, 553, 558, 559, 560, 570 D-2 Macroglobulin in Brn2-ablated cell lines, 157 TYRP1, 553, 559, 560 Macroscopic spectral imaging described, 406 uMAG-A, 553, 565–567 MAGE-1, 621 MART1 MAGE-2, 621 in Brn2-ablated cell lines, 155, 158 MAGE-3. See Melanoma antigen gene (MAGE)-3 in CNS metastases, 571 Magnetic resonance imaging (MRI) of metastasis, MAGE recognition by, 621 552, 571 as molecular marker, 559–562, 570 Major histocompatibility complex (MHC) in in prognosis, 463, 464 immune response, 620, 635, 642 regulation by Mitf, 58, 61, 105–106 MALDI-TOF Mascot software url, 411 history of, 411 Mass spectrometry in proteomics profiling, 410–411 limitations of, 414, 418 Mast factor (MGF) in normal Mammalian models melanocytes, 130 birds. See Avian models chicken. See Chick models MATF (melanoma-associated transcription mice. See Mouse models factor) described, 483 Mitf, 56 MATP/AIM1, regulation by Mitf, 58 M-Mitf, 74 Matrix metalloproteinases (MMPs) proteomics profiling of, 420 about MMPs, 384–385 rats. See Rat models, octamer binding proteins and AP-2D, 491 Sox10, 72 in apoptosis inhibition, 126, 129 Index 665

expression, inducing, 126, 381, 382, 507 density/distribution, 105–106 in melanocyte development, 13 deregulated signaling in, 250–258 as targeted therapy, 546 development of and VM, 539, 540, 545 about, 3–6, 19, 52, 267 MBP (Myelin basic protein) in Brn2-ablated cell and Brn2, 151–153 lines, 157 genes in, 7–10, 32, 38 MC1R. See Melanocortin-1 receptor (MC1R) Mitf in, 10, 18–19, 34–35, 56–59, 76, 252 MCAM/MUC18. See Melanoma cell adhesion PAX3 gene, 9, 17–18, 32, 130–131 molecule (MCAM)/MUC-18 and B-Raf, 557 Mcl-1 in drug resistance, 579 and Rb-E2F, 228–229 MDM2 (murine double-minute 2) protein in cell Sox10 in, 9, 17, 71, 73–74, 76 cycle regulation, 367 transcription factors in, 9–10, 16–19, 32, MDR. See Multidrug resistance (MDR) 158, 482 Mediterranean populations, melanoma in, 330–331 Wnt/E-catenin-signaling pathway, 6, 11–13, MEK–ERK pathway 17, 44, 56 activation of, 121, 251, 254, 274 DNA damage to, UV-induced, 107–111 targeting, 135–136 and environment, 103–107 Melacine, 641, 642 human. See Human melanocytes (hMC) Melan-A/MART-1 lymphocytes, 624 in human pigmentation, 82, 89–90, 176 Melanin imaging, 406 DNA damage associated with, 295 MAAs in, 624 in drug resistance, 598 migration of, 4, 5 as photoprotection, 295, 581 normal, physiological signaling in, 248–249 P-gp in, 595 production of, 102–103, 273 in photoprotection, 82, 83, 169, 248 regulation of, 36, 57, 81 progression, genetic mechanisms of, 203–206 response to UV, 106–107 Rb deficiency in, 233–237 in skin pigmentation, 82–83, 106 response to UVR, 90–91, 105–106 synthesis, 348–349, 514, 581 and skin pigmentation, 28–30, 41, 55, 57–58, and tyrosinase, 83 103–104 Melanoblasts survival of, 57, 82, 84, 92–93, 126, 258 Brn2 levels in, 152, 153 transformation described, 28 about transformation, 619–620 formation of, 3, 4, 18 genetic regulatory mechanisms of, 483, MAGE genes in, 621 490, 491 migration of, 5–6, 12, 13, 28 rates and sunlight, 311 regulation of, 19, 102 vs nevi, 515–517 survival and Mitf, 57 D-Melanocyte-stimulating hormone (D-MSH) Melanocortin-1 receptor (MC1R) and ASIP, 356 about human MC1R, 271, 350–353 and MC1R, 88, 252, 272, 350 and ASIP, 359 in melanin synthesis, 348–349 in Brn2-ablated cell lines, 159 and melanocyte proliferation, 249, 253, 370 in Erk activation, 254 in Mitf regulation, 55, 75–76, 254, 257 and hMC, 88–89 in pigmentation regulation, 81, 82, 85, 88, 248 and melanoma risk, 250, 336, 340, 359–360, 443 synthesis of, 88 D-MSH and, 88, 252, 272, 350 E-Melanocyte-stimulating hormone (E-MSH) in mutations in, 250, 266 pigmentation regulation, 88 and P gene, 359–360 J-Melanocyte-stimulating hormone (J-MSH) in signaling via, 272 pigmentation regulation, 88 in skin pigmentation, 104–105, 248, 271–273, MelanoDerm cultures, response to UVR, 111 349, 353–355 Melanoma variants, predicting, 353 2D-PAGE analysis of, 413–417 Melanocortins and hMC, 88–89 about melanoma, 19, 592, 651 Melanocytes animal models of, 303–304, 316–317 about melanocytes, 3, 81, 82, 102, 247, 514, 522 Brn2 in, 153–155 cadherin shift by, 176–177 cells, properties of, 28, 44 cells, properties of, 28, 169 chromosome/gene changes in, 120, 199, 202–206, cell signaling/adhesion in, 7–13, 42 265, 375–376, 555; see also DNA dendricity of, 92, 104, 267 classification of, 201–203, 267, 430 666 Index

clonal autonomy in, 379, 387 in angiogenesis/vasculogenesis, 536 cutaneous (CMM). See Cutaneous malignant and AP-2D, 489, 491 melanoma (CMM) in bone marrow metastases, 572 development. See Development of melanoma as molecular marker, 553, 555, 565–567 diagnosis. See Diagnosis regulation of, 379, 382–383 and DRC, 446–448 Melanoma cell vaccine (MCV), 625, 640–641 epidemiology of, 442 Melanoma inhibitory activity (MIA) expression of octamer binding proteins in, 151 described, 475–477, 485–486 growth factors in, 378–380 in prognosis, 463, 464 hereditary. See Hereditary (familial) melanoma protein and histological dysplasia, 521 characterization/structure of, 478–481 imaging, 406 expression, effects of, 482 incidence function of, 481–482 by age, 313–314, 316, 321, 322 regulation of, 475 by anatomical site, 313, 314, 316, 651–652 as serum marker, 485 in men, 313, 330, 447 transcriptional regulation of, 482–485 by occupation, 314–315 Melanoma in situ (MIS) described, 522, 523 and radiotherapy, 270 Melanosomes rise in, 265, 266, 291, 369 Dct expression in, 584 in US, 366, 430, 442, 552, 592 in drug resistance, 596, 598 in women, 313, 330, 447 in melanin synthesis, 102–103, 581 misdiagnosis of, 198 movement, regulation of, 91–92 ocular, 202, 595 response to UVR, 111 pediatric, 273, 368 in skin pigmentation, 82, 83, 102 progression. See Progression transfer of, 104 and Rb, 229–233 Melanotransferrin (p97) as molecular marker, recurrence. See Recurrence in melanoma 553, 565–567 regression. See Regression in melanoma MelCAM regulatory pathways in, 378–380 repair deficiencies associated with, 299 in apoptosis inhibition, 126 RGP. See RGP (radial growth phase) melanoma and N-cadherin, 172 risk factors. See Risk factors for melanoma Men development melanoma incidence in, 313, 330, 447 signal pathways in. See Signaling pathways prognosis for, 527 in situ, 522, 523 ulceration in, 458 and Sox10, 77 VMO in, 641 sporadic, 443 Metallopanstimulin-1 (MPS-1) described, 378 susceptibility to. See Susceptibility to melanoma Metallothioneins (MTs) target pathways in, 302–303 in drug resistance, 598 transition, RGP to VGP, 491 in prognosis, 463, 464 tumor, model of, 542 Metastasis uveal. See Uveal melanoma actins in, 383–384 and angiogenesis, 385–388, 503, 504 VGP. See VGP (vertical growth phase) melanoma AP-2 and, 492 and XP, 296 D biology of, 504 Melanoma antigen gene (MAGE)-1, 621 bone marrow, 572–573 MAGE 2 Melanoma antigen gene ( )- , 621 brain, 385 Melanoma antigen gene (MAGE)-3 CNS, 571 about MAGE-3, 621 distant in prognosis, 569–571 in CNS metastases, 571 enzymes in, 385 as marker, 559–562, 565–567 growth requirements of, 379 Melanoma-associated antigens (MAA) imaging, 403–404, 552 classification of, 622 lymph node, 381, 652 expression, detecting, 570 MAGE genes in, 621 immune response to, 619–620, 624, 635, 636 and Met expression, 276 in progression/inhibition of melanoma, 623–626 and MIA, 482 recognition of, 620–623 NF-NB inhibition of, 133, 503 as vaccines, 642 and expression, 375 Melanoma cell adhesion molecule (MCAM)/MUC-18 and PAR-1, 492, 498 Index 667

patterns of in Mek/Erk activation, 253–254 about, 429, 430, 528 in melanocyte development, 10, 18–19, 34–35, pre-SLN era, 430–431 56–59, 76, 252 SLN era, 431–433 in melanocyte function, 105–106 and survival rates, 434 modifications, posttranslational, 38–41, 59 predicting, 185, 377, 416, 417, 430–436, 528, mutations in, 35–37, 74–75 552, 573 and Pax3, 17 and prognosis, 429–436, 468–469, 503–504, and PI3Ks, 258 527, 625 promoter, repression of, 162 in RGP melanoma, 526, 528 protein-protein interactions, 59–61, 248 RhoB, inhibition by, 126 regulation of sites of, most common, 430 described, 60, 71, 122 and staging, 429, 431, 434, 436–437 posttranslational, 37–44 systemic, 429, 430, 432, 433, 435, 438 and Slug, 18 and telomerase activity, 374 Sox10 gene and, 19, 37, 53–55, 71, 74–76 and vascular involvement, 507 in Spitz nevi, 199 and VEGF, 386 stability of, 40, 59 c-Met expression in HGF/SF signaling, 130, 276–277 structure/products of, 31–34 Met expression in Ras transformed cells, 130, 131, transcription of, 34, 272 256–258 Mitfmi–rw allele described, 36 Methotrexate, 578, 580 Mitfmi–sp allele described, 36 Methylation of DNA, 226, 598 Mitfmi–vit allele described, 36, 42 Methyl CpG-mediated transcriptional repression, 216 Mitogenicity O6-Methylguanine DNA methyltransferase (MGMT) defined, 523 in drug resistance, 578 in prognosis, 525, 526 hypermethylation in, 571 Mitosis, inhibiting, 578 as molecular marker, 553, 555, 556, 568 MLANA MeWo cell lines, PAR-1 promoter activity in, in angiogenesis/vasculogenesis, 536 496, 497 in Brn2-ablated cell lines, 155, 158 MGF. See Mast cell growth factor (MGF) regulation by Mitf, 58, 61, 105–106 MGMT. See O6-Methylguanine DNA ML-IAP/livin described, 611 methyltransferase (MGMT) MM96Lc8D cell lines, Brn2 ablation in, 155–158 MIA. See Melanoma inhibitory activity (MIA) MM96Lc8LC cell lines, Brn2 ablation in, 155–159 MIB-1 antibody in cell proliferation, 377 M-Mitf Microsatellites E-catenin/LEF-1/TCF response and, 56 LOH in, 555, 570 cell lineage specificity of, 38, 52 and prognosis, 462, 554–556, 562–563, 568–569 expression of, 35, 36, 53, 74–75 in RGP, 525 regulation of, 37, 53–56 Microtubule inhibition by chemotherapeutic MMPs. See Matrix metalloproteinases (MMPs) agents, 578, 580 Mobility changes, identifying, 413 Migration Molecular studies of melanoma, 317 defined, 522 Monoclonal antibodies (MAbs) in MAA of melanoblasts, 5–6, 12, 13 recognition, 623 Minimal erythema dose (MED) defined, 335 Mouse models Mitfmi-b allele described, 36 Adamts20 gene, 13 Mitf (microphthalmia associated transcription agouti, 355 factor) antisense oligonucleotides, 611 about Mitf, 28–31, 51–52, 62 AP-2D, 490 activation ARF, 187–188, 278 by SKI, 217–218 ATF2, 134 by Wnt, 122 Bcl2, 42 in angiogenesis/vasculogenesis, 536, 538 bFGF, 387 in Brn2-ablated cell lines, 155, 157, 158, 159 B-Raf, 127, 251 in cell proliferation/differentiation, 41–44 Brn2, 38, 153 expression of, 5, 19, 34 cadherins, 12, 170 function of, 29, 52, 93, 129 E-catenin, 12 and Fyn inhibition, 256, 257 CD44, 382 isoforms of, 53 Cdk4, 270 668 Index

CDKN2A, 188–189 Multidrug resistance (MDR) cell senescence, 185 and ABC transporters, 594 cyclin D1, 376 about MDR, 599–600 dacarbazine, 609 causes of, 591, 592 Dct, 76, 581–582, 584 Multiphoton microscopy described, 400 DNA-deficient, 303–304 Mutations doxycycline, 281 B-Raf. See B-Raf mutations Ednrb gene, 14–15 in drug resistance, 593–594 Efnb, 13 fixation of, 444 eicosanoids, 86 frequency differences in, 369 Foxd3, 16 in PAR-1, 496 Fyn, 256 pathways targeted by, 273–278 IFNs, 636 prevalence in melanoma, 556–557, 563–564, 570 Kit, 15–16, 29, 87, 248 proviruses and, 579 limitations of, 303, 317 UV-signature, 280, 301–302, 444 MXI1 in tumor suppression, 277 LOH, 278 c-Myc gene MC1R, 88, 353 in apoptosis modulation, 609, 611, 612 melanoblast migration, 6, 28, 30 in cell crisis, 375 melanoma development, 317 Myc gene in cancer, 61, 120, 128, 279, 375 melanosome transfer, 104 MYO5A gene in Brn2-ablated cell lines, 157, 158 c-Met, 276–277 MIA, 481–482 N Mitf, 31, 36, 52, 57, 257 NAV2 gene in Brn2-ablated cell lines, 157 neural cell migration, 5 Near-infrared (NIR) spectrum probes described, osteopontin, 255 400, 406 p16, 251, 253, 269, 278 Nerve growth factor (NGF) p53, 278–279 in melanocyte protection, 82, 85, 87, 92, 93, 249 Pax3, 17, 37, 56 synthesis of, 84 PTEN, 277 Nest formation in melanocyte transformation, Rb, 283 515, 517, 521, 524 Rb/E2F, 228, 229, 231, 233–237 neu gene in cancer, 375, 491 ribozyme therapy, 505–507 Neural crest cells Ski, 212–215 formation of, 4–6, 56 Snail family genes, 18 marker expression in, 28, 72 Sno, 212, 214 migration of, 6, 11–14 Sox9, 16 Sox10 in, 17, 72, 73 Sox10, 17, 55, 72–73 Neuron development, imaging, 402 Tcfap2D, 18 Neurotrophin-3 (NT-3) in melanocyte survival, tyrosinase mutations, 57 84, 85, 87 UV exposure in melanoma induction, 292, 302 Nevi VGP vs RGP, 525 about nevi, 197, 331, 514 VM, 543, 544 chromosome aberrations in, 199, 200, 205 classification of, 184–185, 189, 197–198 Wnt/E-catenin-signaling pathway, 7, 11, 12 mRNA markers common acquired, 514–515, 519, 527–528 compound defined, 515, 517 about mRNA markers, 553–554, 558 dermal defined, 515 assessing, 436, 559, 562, 622 dysplastic; see also Dysplastic nevus detection syndrome in blood, 564–567 AgNOR expression in, 378 in distant metastases, 570 described, 198, 515–517 MRP1 protein in MDR, 597 DNA repair capacity (DRC), 444, 447 MRP2 protein in MDR, 597–598 imaging, 406 D-MSH. See D-Melanocyte-stimulating hormone immune response to, 634 (D-MSH) in Italian population study, 331–334, 338 MSTag software url, 411 MAGE genes in, 621 MudPIT (Multidimensional protein identification microvessel density in, 387 technology) described, 420–422 as risk factor, 198, 340–341, 442–443, Multicenter Selective Lymphadenectomy Trial 517–521, 527–528 (MSLT)-II described, 562, 573 VEGF in, 386 Index 669

formation of, 248–249 Oculocutaneous albinism type 3 syndrome, 359 genetic basis of, 189–191 Oculocutaneous albinism type 4 syndrome, 58 imaging, 404–406 Oligonucleotides in proteomics profiling, 419 melanin in, 295 OMSSA software url, 411 melanocytes in, 249 in melanoma pathogenesis, 374–377 melanocytic described, 197–201, 376–377, Onecut2 in Mitf regulation, 38 514–521 Opossum models, advantages of, 303 in melanoma risk, 315–316, 321, 322 Optical coherence tomography (OCT) described, MIA in, 476, 477 401–402, 406 misdiagnosis of, 198 Optical imaging mutations in, 189, 518, 557 applications in melanoma, 403–406 number of as risk factor, 519 fundamentals of, 399–402 senescence in, 183, 190 optimizing, 402–403 vs melanocytes, 515–517 Osteonectin Nevi with architectural disorder and cytological in Brn2-ablated cell lines, 157, 159 described, 382 atypia (NAD). See Nevi, dysplastic Osteopetrosis and mitf expression, 36, 59 Nevoid melanomas described, 515 Osteopontin and Mek/Erk, 255 Nevomelanocytes. See Nevi NF-NB signaling pathway P about NF-NB, 614 p14ARF in melanoma, 231, 303, 337 activation of, 121, 125, 126 p16INK4A–cyclin D–CDK4/6–RB pathway in in drug resistance, 585, 598, 609 melanoma development, 268–270, 337 in metastasis, 503, 506–507 p16INK4A protein; see also CDKN2A regulation of, 132–133 in benign nevi, 190 as therapy target, 612 encoding of, 303 in tumor invasiveness, 508–510 expression, measuring, 369 NGF. See Nerve growth factor (NGF) function of, 269, 339, 367–370 Nitrosoureas, response rate as single agent, 592 inactivation of, 228, 268, 275 Nodal status and clinical outcome, 430 location of, 366 Nodular melanoma (NM) described, 201–202 in melanoma susceptibility. See Susceptibility Northern European descent, MC1R variants in, to melanoma 350, 353 in nevi senescence, 183 Notch signaling and apoptosis, 544, 545 in senescence, 185, 186, 188–189, 205, 268–270 Nr-CAM activation by SKI, 217–218 in Spitz nevi, 199, 201, 275 NSC 73306 in MDR modulation, 599 as therapy target, 280 NT-3. See Neurotrophin-3 (NT-3) and UVR in melanoma development, 270, Nuclear receptor co-repressor (N-CoR) protein in 279, 303 transcriptional repression, 215 p16 protein Nucleotide excision repair (NER) as molecular marker, 553, 555 cleavage efficiency in, 293 and prognosis, 463 deficiencies, consequences of, 295–296 p19ARF gene and p53 gene mutations, 236 mechanisms, 296–299 p21 protein and AP-2 , 490, 491 in melanoma development, 292, 444–449 D in cell cycle regulation, 367, 372 of UV-induced DNA damage, 293–295 and CKI activity, 228 Number of nodes in prognosis, 464–465 in M1 senescence, 185, 188 NY-ESO-1 gene, expression of, 622 in metastatic melanoma, 231, 232, 236 O in TGF-E repression, 216 in UV damaged DNA, 299 OBF1 interactions, 162 p27 protein Occupation and melanoma incidence, 314–315 and CKI activity, 228 Oct-1 factor, cellular expression of, 150, 162 expression and Mitf, 42 Oct-2 factor, DNA binding in, 151, 162 and Rb/E2F, 231 Octamer binding proteins, expression of, 151 regulation of, 381 Ocular melanoma, 202, 595 p38 gene Oculocutaneous albinism type 1 syndrome, 57, activation by TRAF proteins, 132, 134 103, 155 in drug resistance, 585 Oculocutaneous albinism type 2 syndrome, 357, stress kinase and Mitf regulation, 40 359–360 and tyrosinase expression, 248 670 Index p53 gene Periodic acid-Schiff (PAS) staining in VM imaging, and ARF, 271 534, 537, 539, 541, 543 in benign nevi, 190 Peutz Jeghers syndrome described, 277 CLDC based therapy and, 505 P-glycoprotein (P-gp) in drug resistance, 592–595, clinical trials of, 613 599; see also ABC transporters in drug in DNA repair, 296, 298, 299, 302 resistance in drug resistance, 578, 598, 608 Phenotype mouse models of, 278–279 DRC and melanoma risk, 444, 448 mutations in melanoma development MC1R associations with, 353–355 apoptosis-inducing, 337, 370–372 MDR, ABCC subfamily in, 597–599 and p19ARF, 236 and melanoma risk, 348, 369, 370 senescence and, 185–188, 191–193 metastatic, 375, 385–388 UV-specific, 318, 444 pigmentation and XP, 296 P protein gene and, 352, 357–358 and prognosis, 463 and tyrosinase, 352, 358 in senescence, 206, 370 and prognosis, 526–527 suppressing, 228, 231, 269, 367 RHC with UV signatures, 292, 444 and melanoma risk, 271–273, 291, 336, p53–Mdm2 negative feedback loop, imaging, 403 353–354 p65 protein P gene in, 360 and metastasis, 506–507, 509 and telomerase activity, 373 in MIA inhibition, 484 VM, 537–539, 545 and tumor vascularization, 503 Pheomelanin , repression of, 236 and ASIP, 349 p75 nerve growth factor receptor, 385 and cancer risk, 273 p97 (melanotransferrin) as molecular marker, DNA damage via, 295 553, 565–567 and photoprotection, 333, 348 p107 in Rb/E2F, 228–230, 238 in skin color regulation, 82, 581 p130 in Rb/E2F, 228–230, 238 synthesis, 88, 273, 355 p300 and Brn2, 161 PHLDA1 gene in apoptosis resistance, 612 Paclitaxel Phosphatidylinositides in array-based proteomics, 419 mechanism of action, 578 Phosphorylation resistance to, 58 of E-Catenin, 120, 174 response rate as single agent, 592 CREB, 37–38, 93, 272 Pagetoid pattern described, 521, 522, 524 of Mitf, 33, 38–40, 56, 59, 60 Papillary renal cell carcinomas, 61 paxillin, 87 PAR-1. See Protease-activated receptor (PAR)-1 of Rb protein, 130, 268, 269 PAR-21. See Protease-activated receptor (PAR)-2 of serines, 226 in melanosome transfer of threonine, 120, 226 Paracrine factors Photoprotection, melanocytes in, 82, 83, 169, 248 in cell-cell signaling, 119–123, 274 PI3K (Phosphatidylinositol-3 Kinase) pathway in skin pigmentation, 83–87, 91, 92, 93, about, 123–126 105–106, 248 Akt signaling, 256–258 in VGP, 379 and PAR-1, 492 PAS (Periodic acid-Schiff) staining in VM imaging, pathway interactions with, 135, 174, 232–233 534, 537, 539, 541, 543 and PTEN, 277, 318–319 PAX3 (Paired homeodomain transcription factor targeting, 136 3) gene in VM, 539 in Brn2-ablated cell lines, 158, 160–161 PIAS3 protein and Mitf regulation, 39, 59–60 function of, 29, 130 Piebaldism, 87 in melanocyte development, 9, 17–18, 32, Pigmentation 130–131 in Brn2-ablated cell lines, 155, 158 and Mitf expression, 19, 37, 53, 54–56, 75, 158 cutaneous as molecular marker, 553, 555, 559–562 in humans, 82–83 Paxillin phosphorylation and SCF, 87 measuring, 334–336 PDGF. See Platelet-derived growth factor (PDGF) melanin synthesis/distribution, 82–83 PeptideSearch software url, 411 melanocytes and, 28–30, 41, 55, 57–58, Performance status in prognosis, 469 103–104 Index 671

and melanoma risk, 354, 356–357, 442, 447 gender and, 460, 461, 469 regulation of, 81, 83–87, 89–90, 101, 102, 107 invasion of tumor cells in, 459 role of, 82, 340, 341 and MAA antibodies, 624–626 development of, 28–30, 41, 55, 57–58, 72 and metastasis, 429–436, 468–469, 503–504, gene interactions in, 359–360 527, 625 and MAAs, 624 microsatellites and, 462 and MC1R, 271–273, 351–352 number of nodes in, 464–466 phenotype and melanoma risk, 348, 369, 370 regression and, 462 UV-induced, 81, 82, 83, 90–92, 102, 248, 348 thickness of tumor and and UV sensitivity, 334–336 classification of, 457 Pit-1 factor, cellular expression of, 150 genetic abnormalities, identifying, 554 PKCI/HINT1 and Mitf regulation, 60–61 mortality rates, 458, 460–462 Plasticity of cells and vascular mimicry, 534–537, survival, predicting, 467, 508, 513, 527 544, 545 TMR in, 460–461 Platelet-derived growth factor (PDGF) vascular density and, 462 and PAR-1, 492 vascular factors in, 507–509 in VGP melanoma, 379 and vascular mimicry, 534, 541 Platelet endothelial cell-adhesion molecule-1 in Programmed cell death. See Apoptosis cell adhesion/invasion, 507 Progression Pmel17 gene in bone marrow metastases, 572 about progression, 431–432, 490, 513–514 MAGE recognition by, 621 hypermethylation in, 556 Pocket proteins and immune response, 619–620 described, 224 inhibiting, 609, 610 inactivation of, 229 and MAAs, 623–626 Pol-K in DNA repair, 301, 302 molecular basis of, 521–527, 544–546 Pol II in DNA damage repair, 298, 299 Progression, genetic basis of Pol-L in DNA repair, 301, 302 about progression, 184, 192–193, 366–370, 409 Polymerase chain reaction (PCR) and cell senescence, 185–187, 189 in molecular staging, 436–437 Clark model RT-PCR. See RT-PCR described, 184–185, 189, 459, 514 Polymorphisms in melanoma genetic basis for, 189–191 ASIP g.8818A/G, 356 markers. See Markers DRC, 448–449 mechanisms, 203–206, 525 germline, 265, 269 PAR-1, 491–498 GST, 443–444 SKI protein, 212–215 MC1R. See Melanocortin-1 receptor (MC1R) stages and expression of proteins, 415–417, 482 testing, 350, 443 vascular factors in, 507–508, 533–537 Positron emission technology (PET), 552 Proliferating cell nuclear antigen (PCNA) Posttranscriptional regulation of Mitf, 38–41, 59 described, 377 POU domain transcription factors and p53 expression, 372 in cell regulation, 149 Proliferation mechanisms DNA binding in, 150–154 genetic in melanoma, 203–206 in Mek/Erk activation, 254–255 and Mek/Erk, 253 and Sox family genes, 161 in nevi, 199–201 P protein (pinkeyed dilution) gene Promyelocytic leukemia protein (PML) and melanoma risk, 360 in senescence, 217 and pigmentation phenotypes, 352, 357–358 Proopiomelanocortin (POMC), synthesis of, 88 PQBP-1 and Brn2, 161 Prostaglandins, hMC response to, 85–86 Prevalence. See Incidence of melanoma Prognosis Protease-activated receptor (PAR)-1 and age, 460, 461, 467, 469 about, 489, 498 and anatomical site, 460, 461, 467, 527 DNA binding in, 492–493 distant metastasis in, 569–571 expression, regulating, 493–497 factors influencing gene regulation by, 496–497 about, 455–456, 469–470, 513 in melanoma progression, 491–498 stage 1/2, 456–464 promoter, deletion analysis of, 495–496 stage 3, 464–468 Protease-activated receptor (PAR)-2 in melano- stage 4, 468–469, 634 some transfer, 91 672 Index

Protease activity, extracellular, 417, 418 frequency and melanoma type, 203 Protein identification in Mek/Erk activation, 251, 252, 254 2D-PAGE. See 2D-PAGE in melanocyte transformation, 557 about, 409–412 in melanoma maintenance, 282 low-abundance, 420, 421 in melanoma pathogenesis, 275–276, 319 MudPIT, 409–412 as molecular marker, 191, 553 SELDI. See SELDI in nevi, 189, 198–199, 518 Protein kinase C (PKC) pathway interactions with, 127–129, 135, 233 activation of, 121 and PTEN, 256 and PAR-1, 492 signal transduction via, 121, 122 and Wnt5a, 123 and sun exposure, 376 Protein kinases, proteomics profiling of, 419 targeting in treatment, 136 Protein phenotype and cell line classification, RAF proteins in MAPK activation, 275–276 416–417 Random nuclear atypia described, 517 Protein pockets. See Pocket proteins Raper-Mason scheme, 102 Protein tyrosine kinases (PTKs), 374 H-Ras Proteomics profiling clinical trials of, 613 about, 409–411 in melanocytic nevi, 199 activity-based, 417 mutations array-based, 419–420 in melanoma proliferation, 275–276, 375 and bioinformatics, 422 in Spitz nevi, 376 and VEGF, 282 bottom-up (shotgun), 420–422 RAS association domain family protein 1A (RASSF1A) Proto-oncogenes in melanoma pathogenesis, 120, hypermethylation in, 564, 570–571, 571 374–377 as molecular marker, 553, 555, 556, 568 Proviruses and mutations, 579 Ras gene Psoriasis and DRC, 446 clinical trials of, 613 PTEN gene in drug resistance, 598, 608–610 in melanoma pathogenesis, 121, 123–124, Fas 128, 192, 277–278, 318–319 in regulation, 374 in pathway interactions, 135 in melanoma maintenance, 281–282 and PI3K/Akt, 256, 277 mutations PTKs. See Protein tyrosine kinases (PTKs) in Mek/Erk activation, 252 PU.1 and Mitf regulation, 59 in melanoma pathogenesis, 128, 130, 275–276, 444 Q in nevi, 198–199, 518 Quadrupole instruments described, 410 and B-Raf, 127 Quantification pathway interactions with, 135, 232, 233, 251, in 2D-PAGE, 412–415 254, 274 in MudPIT, 422 proteins, function of, 127 and PTEN, 256 R senescence, resistance to, 370 Rab5E in Brn2-ablated cell lines, 157 signal transduction in, 121, 557 Rab25 in Brn2-ablated cell lines, 157 transformation and LKB1, 278 Rab27a in Brn2-ablated cell lines, 157, 158 K-Ras mutations Rab38 gene, 155, 157 in melanoma proliferation, 275 Radial growth-phase (RGP) melanoma. See RGP and VEGF, 282 (radial growth phase) melanoma N-Ras mutations Radiotherapy in drug resistance, 609 about radiotherapy, 578–579, 591 in melanoma proliferation, 189, 191, 223, 275, 319 and melanoma incidence, 270 in RGP/VGP melanoma, 523 resistance and V599E B-RAS, 276 Dct, 577, 583, 585–586 RAS/RAF/MEK/ERK Pathway p53 in, 608 described, 251–255 B-Raf mutations and MAPK activation, 274 about B-Raf mutations, 303, 609 RASSF1A. See RAS association domain family and Brn2 expression, 154, 255 protein 1A (RASSF1A) and CDK activity, 223 Rat models, octamer binding proteins, 151 in distant metastases, 570 Reactive oxygen species in melanogenesis, 348 in drug resistance, 598 Receptor tyrosine kinases (RTKs) Index 673

activation of, 86–87, 274 Retroviral insertional mutagenesis described, and Brn2 expression, 122 579–580, 583 and cadherins, 169, 177–178 RGP (radial growth phase) melanoma in melanomas, 233, 250 about RGP, 185, 267, 416, 514, 523–525 in signal pathway activation, 275, 636 apoptosis in, 190–191 in VM, 539 B-cell antigen in, 623 Recurrence in melanoma biology of, 525–526 and immune response, 620 HLA-DR in, 635 lymph nodes, 430, 557, 560 mutations in, 127, 128 and P-gp expression, 595 prognosis, 513, 526 predicting, 377, 403, 564–567 RHC phenotype and TA90, 626 and melanoma risk, 271–273, 291, 336, 353–354 types of, 204–205 P gene in, 360 vascular factors in, 508 Rho kinases Regression in melanoma and apoptosis, 206 deregulation of, 259 immune-mediated, 635–636, 639 metastases, inhibition by, 126 and immune response, 620, 625–626 and PAR-1, 492 and metastasis, 430 Ribozyme therapy, 505–507 and prognosis, 462 Risk factors for melanoma development; see also spontaneous, 596, 633, 634 UV radiation; Xeroderma pigmentosum (XP) RelA, clinical trials of, 613 described, 319–320, 331–340 Relapse, detecting, 403 dysplastic nevi, 198, 340–341, 442–443, Rel family described, 133, 613 517–521, 527–528 Reproducibility MC1R gene mutations, 250 in 2D-PAGE, 412–413 pheomelanin, 273 in MudPIT, 421 RHC phenotype, 271–273, 291, 336, 353–354 Resistance, mechanisms of RNA interference (RNAi) in targeted therapy, about resistance, 578–579, 585, 591–593 136, 155, 579 apoptosis deficiency, 605–606 RPE cells. See Retinal pigment epithelium (RPE) chemotherapy. See Chemotherapy, resistance RPG melanomas. See RGP (radial growth phase) and HSPs, 612 melanoma senescence, 370 transporter-dependent, 594–598 RTKs. See Receptor tyrosine kinases (RTKs) transporter-independent, 598 RT-PCR Ret gene expression and Pax3, 17 in marker development, 558–562 Retinal pigment epithelium (RPE) in prognosis, 464, 468, 564–565 development of, 29, 34–35, 52, 59 quantitative RT-PCR (qRT), 560–562 and Mitf mutants, 31, 42, 44, 58 sensitivity of, 571 and M-Mitf deficiencies, 35 S pigment regulation in, 41 tyrosinase expression in, 57–58 S27 ribosomal protein described, 378 Retinoblastoma (Rb) protein S-100E protein in prognosis, 463, 464 clinical applications, 237–238 Safety margins, effectiveness of, 204 described, 223, 224, 227 San descent, MC1R variants in, 350 functions of, 233–237, 367–370 Sarcoma, risk of and Rb, 270 inactivation of, 187, 279 SB2 cell lines, PAR-1 promoter activity in, 496, 497 in M1 senescence, 185–186 SBCL2 cell line, 2D-PAGE analysis of, 414 melanoma and, 229–233, 268, 269, 270 Scatter factor (SF). See Hepatocyte growth factor phosphorylation of, 130, 268, 269 (HGF)/scatter factor (SF) regulation of, 226–228, 230 SCF. See Stem cell factor (SCF) in senescence, 206 SELDI described, 418–419 and SKI, 215, 216 E-Selectin transcriptional regulation by, 224–226, 237 in angiogenesis/vasculogenesis, 536 and UV mechanisms, 283 regulation of, 134 Retinoic acid receptor-E (RAR-E2) L-Selectin in immunotherapy, 644 hypermethylation in, 564, 571 Selective sentinel lymphadenectomy (SSL), as molecular marker, 553, 555, 556, 568 applications of, 431, 435, 438, 504 674 Index

Senescence Slug gene expression cellular, types/mechanisms, 185–187, 189 in Brn2-ablated cell lines, 157, 158, 159 in fibroblasts, 185, 186, 187, 217 in melanocyte development, 9, 18 hTERT in, 187, 188, 190–192 and Sox10, 17 INK4a/ARF locus, 268–270 INK4A Smac/Diablo, inhibition of, 611–612 p16 protein in, 183, 185, 186, 188–189, Smad proteins in TGF-E repression, 211, 215–216 205, 268–270 Snai2/Slug gene p53 gene in, 206, 370 in melanocyte development, 9, 18 PML in, 217 premature (oncogene-induced), 201 promoter regulation by Mitf, 58–59 Rb protein in, 185–186, 206 regulation of, 158 resistance to, 370 SnoN protein telomeres in, 185, 187, 190–191, 205–206, in breast cancer, 212 373–374 functions of, 212, 216 and UVR, 370 structure of, 212 Sensory neurons, induction of, 12 in TGF-E repression, 211 Sentinel lymph nodes (SLNs) Software for MS/MS data analysis, 411 marker expression, detecting, 562 Solar keratoses in melanoma development, 321, 322 in metastasis, 430–433, 552 Sox6 protein in MIA inhibition, 484 in prognosis, 557–558 Sox9 gene in melanocyte development, 9, 16–17 sampling method, 559 Sox10 gene in staging, 456, 573 in Brn2-ablated cell lines, 157, 158, 159 and survivin, 611 function of, 29, 71–73, 76–77 Serines in Mitf phosphorylation, 33, 38–40, 59, 60 in melanocyte development, 9, 17, 71, 73–74, 76 phosphorylation of, 226 in melanoma, 77 Serological techniques in MAA classification, 622 and Mitf expression, 19, 37, 53–55, 71, 74–76, 158 SH3 domains described, 478, 480, 481 and D-MSH, 76 Shedding phenotype described, 417 mutations in, 75 Shotgun (bottom-up) proteomics profiling, 420–422 promoter, regulation by Brn2, 162 Signaling pathways; see also individual pathway Sox family genes and POU domain transcription by name factors, 161 about signaling pathways, 258–259 Sp1 transcription factor activation described, 493–494 and HGF/SF, 274, 276–277 in PAR-1 regulation, 494–497 and RTKs, 275, 636 SPARC. See Osteonectin altered and apoptosis, 125, 126, 132, 217–218 Specificity protein (Sp)-1, 489 autocrine factors in, 250, 256–257 balance alterations in, 415 Spitz nevi bFGF in, 250, 384 AgNOR expression in, 378 HGF in, 250, 256–257, 274 described, 198–199, 201 interleukins in, 250, 378, 379 genomic instability in, 376–377 in melanoma H-Ras amplification in, 275–276 alteration of, 121, 128 E-integrins in, 381 mutations targeted by, 273–278 VEGF in, 386 targeting in treatment, 135–136 Splice forms, Mitf, 53 paracrine factors in, 119–123, 274 Src kinases stress response, 585 and Cortactin, 256, 257 VM, 539, 540, 544, 545, 546 in immune response, 636 Silver staining in proteomics profiling, 412 in Mek/Erk, 255–256 SILV/Pmel17/GP100 Sry-box in Sox protein binding, 71 in Brn2-ablated cell lines, 155, 157, 158 SSX2 gene, expression of, 622 regulation by Mitf, 58 Staging of melanoma c-Ski gene, 212, 216; see also SKI protein AJCC guidelines, 455–456, 459, 508, 513, Skin pigmentation. See Pigmentation, cutaneous 528, 569 SKI protein and metastasis, 429, 431, 434, 436–437 described, 211–212 PCR in, 436–437 functions of, 215–218 and prognosis, 625 structure of, 212–215 SLNs in, 456, 573 as targeted therapy, 218–219 STAT1, function of, 131, 636 Index 675

STAT3 Suv39H1 and Rb transcription, 225 in drug resistance, 598 SYCP-1 gene, expression of, 622 and Mitf, 62 Synergy in Sox10/Mitf binding, 76–77 in tumor cell lines, 131 STAT proteins T in apoptosis inhibition, 125, 126, 129 TA90 protein deregulation of, 259 about TA90, 624 described, 131–132 in prognosis, 624–626 imaging, 406 Tamoxifen Steel factor. See Kitl expression Stem cell factor (SCF) in chemotherapy regimens, 598–599 in apoptosis inhibition, 188 and IFND2b, 637 in Brn2 expression, 154 Tanning response in Brn2 induction, 255 and melanoma risk, 442, 447 in melanocyte protection, 82, 85 regulation of, 81, 82, 105 in melanoma proliferation, 379, 380 study definition of, 331 synthesis of, 84, 86–87 TAP1/TAP2 (ABCB2/ABCB3) expression in in UV-induced melanogenesis, 248, 249, 252 melanoma, 595–596 and UVR-induced apoptosis, 93 Taxanes, response rate as single agent, 592 Stem cell retrovirus, restriction map of, 579 TBF-E, Transforming growth factor E (TGF-E) Stress in drug resistance, 585 TBP and Brn2, 161 Sub-Saharan descent, MC1R variants in, 350 Tbx2, regulation by Mitf, 58 Sumoylation in transcription factor activity, 40 T-cell factor (TCF) and MIA inhibition, 483–484 Sunburns as risk factor, 279, 280, 442, 519 T-cells Sunlight exposure as risk factor, 202–203, 265, anergy, inducting, 635 266, 441–444 responses to melanoma, 620–622, 624, 635–636 Superficial spreading melanoma (SSM) Tcfap2 gene in melanocyte development, 9, 18 described, 201–203, 205 D growth pattern in, 462, 521, 522 TCR. See Transcription coupled repair (TCR) Survival rates; see also Prognosis Telomerase in cell immortality, 373–374 detection via molecular markers, 560–562, 572 Telomeres factors influencing in cell senescence, 185, 187, 190–191, 205–206, about, 455–456, 469–470, 513, 552 373–374 stage 1/2, 456–464 function of, 373 stage 3, 464–468 Tenascin and cell adhesion, 482 stage 4, 468–469, 634 Texas study of melanoma, 447–448 IFN therapy, 637, 638, 641 TFE3 in cancer, 61 MCV, 640, 641 TFEB transcription factor, 52, 61 and metastasis, 429–436, 503–504, 527, 592 TFEC transcription factor described, 52 predicting, 565 TFIIB and Brn2, 161 TA90 and, 624–626 Therapy; see also Chemotherapy; Radiotherapy vascular factors in, 507–509 about therapy, 578–579, 613 VMO, 641, 642 adjuvant, 434, 504, 551, 566, 572 Survivin gene, 504–505 about survivin, 611 protective, 332 clinical trials of, 613 resistance, overcoming, 134, 283, 545, in drug resistance, 579, 600, 608 585–586, 592 Susceptibility to melanoma ribozyme, 505–507 CDH1 gene in, 338 surgical resection, 435 CDK4, 187, 231, 266, 268–270, 337–339 targeted CMM4, 187 angiogenesis, 545–546 conferring, 187, 317 apoptosis inhibitors, 600 genes involved in, 443 genes as, 280–282 L65P mutant in, 338, 339 liposomal, 375 p16INK4A protein MAA-derived peptides, 621–622, 624 and CDK activity, 223, 226, 238, 337 NF-NB signaling pathway, 612 deficiency in melanocyte transformation, 251 RNAi, 136, 155 mutations in, 187, 231, 368 SKI, 218–219 in nevus formation, 249, 253 Thickness of tumor and prognosis predicting, 340, 449 classification of, 457 676 Index

genetic abnormalities, identifying, 554 TRPM1/Melastatin1, regulation by Mitf, 58, 61 mortality rates, 458, 460–462 Tubulin binding by chemotherapeutic agents, survival, predicting, 467, 508, 513, 527 578, 580 Threonine, phosphorylation of, 120, 226 Tumor, model of, 542 Thromboxanes, hMC response to, 85–86 Tumor burden in prognosis, 465–467, 651 Tie pathway in angiogenesis, 386 Tumorigenicity defined, 523, 526 TILs. See Tumor-infiltrating lymphocytes (TILs) Tumor-infiltrating lymphocytes (TILs) Time-of-flight (TOF) instruments described, 410 in antigen recognition, 633, 635–636 TIMP3 (Tissue inhibitor of metallo-proteinase-3) in immunotherapy, 643–644 in Brn2-ablated cell lines, 157, 159 in prognosis, 461–462, 634 as molecular marker, 553, 555 Tumor lysate vaccines, 641–642 TIMPs (tissue inhibitors of metalloproteinases) Tumor maintenance, concept of, 281 regulation of, 384, 385 Tumor mitotic rate (TMR) in prognosis, 460–461 in VM, 540 Tumor necrosis factor- (TNF- ) Tissue autofluorescence in optical imaging, 400 D D Topoisomerase inhibitors, inhibition of, 609 apoptosis by, 385, 612 Total lymphocyte infiltration (TIL), 525, 526 in drug resistance, 585, 598, 609 TP53. See p53 gene in melanocyte proliferation, 379–380, 384 TRAF2 interactions in cell regulation, 132, 133 in regression, 634 TRAF (tumor necrosis factor receptor-associated regulation of, 132, 134, 378 factors) in apoptosis inhibition, 125, in skin inflammation, 84–85, 92 132–134, 612 Tumor necrosis factor receptor (TNFR) super- TRAIL in apoptosis, 612, 636 family in cell regulation, 132–134, 385 TRAIL-R1 in apoptosis, 606 Tumor-suppressor genes in melanoma pathogenesis, TRAIL-R2 in apoptosis, 606, 609 120, 122 Transcription Tumor thickness. See Thickness of tumor and by E2F family proteins, 224–226, 268 prognosis factors. See Transcription factors Tumor ulceration and prognosis, 458–460, 466–467, by Rb proteins, 224–226, 237 508, 509 regulating, PAR-1, 493–495 Two-dimensional PAGE repressing, 216, 226 gel quality and quantification in, 412–415 Transcription-coupled repair (TCR) in proteomics profiling, 410–412 described, 294, 296 1205Lu cell line, 2D-PAGE analysis of, 417 mechanism, 298–299 Two-hit model for cancer development, 224 Transcription factors; see also individual factor Tyrosinase by name in angiogenesis/vasculogenesis, 536, 538 bHLHLZ. See bHLHLZ (basic helix–loop–helix– and ASIP, 355 ) transcription factors and BMP-2, 14 in cellular senescence, 186–187 in bone marrow metastases, 572 in melanoblast regulation, 6 in Brn2-ablated cell lines, 155, 158 in melanocyte development, 9–10, 16–19, 32, in CNS metastases, 571 158, 482 detection in blood, 564–565 and mitf expression, 36, 40, 43 and eicosanoids, 86 POU domain in cell regulation, 149–150 expression of, 15, 28–29, 253 regulation of, 61–62 and Fyn inhibition, 256 sumoylation in, 40 gene locus of, 581 Transdifferentiation, 545 in immunotherapy, 583 Transforming growth factor D (TGF-D) inhibition by IL-1, 378 and AP-2D, 491 MAGE recognition by, 621 Transforming growth factor E (TGF-E) and melanin content, 83, 102–103, 105–106, 581 in E-integrin regulation, 381 and Mitf expression, 55, 57, 248 in cell signaling, 250 as molecular marker, 553, 558, 559, 560, 570 in CXCR4 expression, 385 in molecular staging, 436 in immune response, 635 and pigmentation phenotypes, 352, 358 in melanocyte inhibition, 84–85, 135, 379–380 in prognosis, 463, 464 regulation of, 134 transcriptional regulation of, 272, 349 repression of, 211, 215–216 Tyrosinase promoter 2 (TYRP2). See in VGP melanoma, 379 Dopachrome-tautomerase (Dct) Index 677

Tyrosinase-related protein (TYRP1) Vaccinia Melanoma Oncolysate (VMO) vaccine, 641 in angiogenesis/vasculogenesis, 536, 538 Validation in shotgun proteomics, 421 and ASIP, 355 Vascular density and prognosis, 462 in bone marrow metastases, 572 Vascular endothelial growth factor (VEGF) in Brn2-ablated cell lines, 155, 157, 158 in angiogenesis, 386–387, 509, 536, 543, 609 in drug resistance, 584 and AP-2D, 491 expression of, 248, 253, 358–359 in immune response, 635 gene locus/function of, 581 PTKs and, 374 MAGE recognition by, 621 and Ras mutations, 282 in melanin production, 102, 105–106, 349 Vascular factors as molecular marker, 553, 559, 560 analysis, molecular, 509–510 and PI3K, 256 in melanoma progression, 507–509, 533–537 repression of, 162 Vasculogenesis Tyr-RAS+, Ink4a/Arf –/– model, 281–282 VE-Cadherin in, 536, 538, 539, 540, 545–546 U collagens in, 536 described, 534–536 UBC9 and Mitf regulation, 59 EphA2 and, 536, 538, 539, 540, 545–546 Ulceration of tumor fibronectin in, 536 and prognosis, 458–460, 466–467, 508, 509 laminin in, 536, 538, 539, 541, 543, 545 in RGP, 525 MCAM/MUC-18, 536 Universal MAGE-A (uMAG-A), 553, 565–567 Mitf, 536, 538 Urokinase plasminogen activation (uPA), MLANA in, 536 regulation of, 129 Uveal melanoma E-Selectin and, 536 gene expression in, 533–534, 537 in tumor networks, 541–543 Ki-67 expression in, 377 tyrosinase and, 536, 538 lymphatic vessels in, 543 and TYRP1, 536, 538 and MC1R, 354–355 Vasculogenic mimicry (VM) molecular studies of, 541–543 biological implications of, 539, 541–544 UV radiation described, 533–537 in apoptosis, 108, 110–112, 247, 249, 583, 585 inhibiting, 545–546 DNA damage via, 107–111, 128, 250, 293–295, phenotype, 537–539, 545 348, 583 signaling cascade, 539, 540, 544, 545, 546 and MAPK activation, 154 VGP (vertical growth phase) melanoma melanin response to, 106–107 about VGP, 185, 267, 416, 514, 523–525 and melanocyte density/distribution, 105–106 apoptosis suppression in, 191–192 and melanocyte function, 105–106 biology of, 525–526 in melanoma development growth requirements of, 379, 385 incidence, rise in, 265, 266, 291, 369 HLA-DR in, 635 molecular basis of, 279–280, 291, 292, 442–444 prognosis, 513, 526–527 and p16INK4A, 270, 279, 303 Vimentin in cell adhesion, 383, 384 mutagenesis via, 301–302, 368 Vinblastine and the Rb pathway, 283 in chemotherapy regimens, 599 and senescence, 370 mechanism of action, 578 sensitivity to and pigmentation, 334–336 response rate as single agent, 592 signature mutations, 280, 292, 301–302, 444 Vinca alkaloids, response rate as single agent, 592 and skin pigmentation, 81, 82, 83, 90–92, 102, 248 Vincristine, response rate as single agent, 592 V Vitiligo, autoimmune-based, 77 Vitronectin receptor, regulation of, 380–381 V599E B-Raf allele in melanoma cell lines, VM. See Vasculogenic mimicry (VM) 127–128, 135–136, 276 Vaccines W CT genes, 622 Waardenburg-Hirschsprung disease and Sox10, 73 and Dct, 584 Waardenburg-Klein Syndrome and Mitf expression, 53 defined antigen, 642 Waardenburg-Shah Syndrome and Mitf expression, 53 ganglioside, 637 Waardenburg syndrome in immunotherapy, 639–640 described, 53, 73, 130, 158 tumor lysate, 641–642 genes causing, 159 whole tumor cell, 640–641 Mitf expression in, 29, 40, 52, 59 678 Index

White spotting in Kit heterozygotes, 38, 40, 87 neural cell development, 4, 12 Whole tumor cell vaccines, 640–641 Snail family genes, 18 WM266-4-AP-2 cell lines, PAR-1 promoter Sox9, 16 activity in, 495, 496, 497 Sox10, 17, 72 WM266-4 cell lines, PAR-1 promoter activity in, Xeroderma pigmentosum (XP) 495, 496, 497 described, 295–296 WM793 cell line, 2D-PAGE analysis of, 417 genes in DNA repair, 298–299 Wnt1 gene mutations in, 301, 441 described, 119–120, 122 and NER defects, 292, 444 and Frizzled receptors, 173 in pediatric melanoma, 273 Wnt3a gene and Frizzled receptors, 173 Xmrk receptor in hereditary melanoma, 250, 253–256 Wnt5a expression in melanoma, 121–123, 155, 176 XPC/HR23B complex in DNA repair, 296–297, 448 Wnt/E-catenin-signaling pathway XPD gene expression in melanoma risk, 334, 448 about, 119–123 XPE (DDB1/DDB2) in DNA repair, 296–297 and Brn2 expression, 154–155 XPF repair enzyme in drug resistance, 578 deregulation of, 259 XRCC1 and Frizzled receptors, 120, 121, 123, 173–176 in BER, 300 gene ablation, consequences of, 173 polymorphisms in, 449 in melanocyte development, 6, 11–13, 17, 44, 56 XRCC3 and Mitf expression, 19, 37, 40, 56, 75, 76 induction of, 299 pathway interactions with, 135, 173–176 polymorphisms in, 449 SKI expression in, 217–218 in skin pigmentation, 104 Y–Z Wnts gene in melanocyte development, 7 Yes, function of, 256 Women Zebrafish models melanoma incidence in, 313, 330, 447 Kit, 16 prognosis for, 527 ulceration in, 458 Mitf, 19, 35, 52, 56, 74–75 neural crest cell derivatives, 11 X Pax3, 17 Xenopus models Snail family genes, 18 Foxd3, 16 Sox10 in, 17, 73, 76 Mitf, 35 Tcfap2D, 18