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Invasion and Metastasis.Pptx 4/20/15 Invasion and Metastasis 6 Hallmarks of Cancer • Most, if not all cancers have acquired same set of func;onal capabili;es during their development, albeit through various mechanisms • Invasion and Metastasis most heterogeneous and poorly understood • Means of achieving all six hallmarks will vary significantly, both Moving Out mechanistically and chronologically • Thus, the order in which these 90% of Paent deaths are due to capabilities are acquired seems likely be quite variable across the non-primary tumors spectrum of cancer types and • Size of all tumors are difficult to subtypes. detect • Moreover, in some tumors, a particular genetic lesion may confer – Brain vs peritoneal/pleural space several capabilities simultaneously, • decreasing the number of distinct Compromising vital func;ons – mutational steps required to blocK passage of product, lung complete tumorigenesis. func;on, bone break • In other tumors, a capability may only be acquired through the • Seed and soil – metastasis form collaboration of two or more distinct micrometastasis in distal sites, genetic changes, thereby increasing fer;le ground allows tumors to the total number necessary for completion of tumor progression. thrive • Thus, in the eight-step pathway – Breast -> brain, liver bones and shown, invasion/metastasis and lungs F deoxyglucose labeling of resistance to apoptosis are each metabolically ac;ve ;ssue – brain acquired in two steps. – Colon -> liver and tumors – highligh;ng metastac disease from non-HodgKin;s – Prostate -> bones lymphoma Which View? Cancer Staging • Historical bias of cancer – Staging is used to determine the severity of the cancer – use TMN staging system • Tumor – size extent and locaon (0-4) homogeneous tumor cells • Nodes – lymph node involvement (0-3) break free from basal • Metastasis – Presence or absence of distant metastasis (0 or 1) membrane to form metastasis Primary Tumor (T) TX Tumor cannot be evaluated T0 No evidence of primary tumor Tis Carcinoma in situ (early cancer that has not spread locally) T1, T2, T3, T4 Size and/or extent of tumor Regional Lymph Nodes (N) NX Nodes cannot be evaluated • Tumors are complex ;ssues: N0 No nodal involvement conscrip;on of normal stromal N1, N2, N3 Nodal involvement (number/extent of spread) and inflammaon cells to act as Distant Metastasis (M) MX Cannot be evaluated M0 No evidence of metastasis collaborators of neoplasmic M1 Metastasis A number may be added to programing. each le_er to indicate size or spread of tumor A T3N2M0 tumor is large, with local nodes but no evidence of metastasis 1 4/20/15 • Most cancers can be assigned TNM classificaon. CNS tumours are classified according to cell type and grade, lymphomas have a different staging system and and hematological malignancies are considered Examples differently again. • For many cancers, TNM designaons correspond to one of five stages. Criteria for stages differ for different types of cancer. For example in bladder cancer T3 N0 M0 is stage III; however; in colon cancer T3 N0 M0 is stage II. Stage Definion Stage 0 Carcinoma in situ (early cancer that is present only in the layer of cells in which it began) Stage I Stage II Higher numbers indicate more extensive disease: greater tumor Stage III size, and/or spread of the cancer to nearby lymph nodes and/or organs adjacent to the primary tumor Stage IV The cancer has spread to another organ. Invasion and Metastasis: Breaching the BM Invasion – Metastasis Cascade • Angiogenesis begins before BM is degraded • But once invading through BM carcinomas gain access to stromal cells, agonists and be_er involvement with blood vessels and lymphac system • Loss of BM can predict future course of metastac disease High grade carcinomas T3 and correlaon • 80% of most aggressive cancers occur in with BM loss. Survival aer surgical removal epithelial cells yielding carcinomas. of primary tumor • Carcinomas begin on epithelial side of A) Less aggressive/differen;ated colorectal BM and are benign un;l they breach BM carcinoma islands (red an; cytoKeran Ab) and BM (green laminin Ab). Stromal • BM = Extra cellular matrix – produced by cells are not labeled (blacK) B) Less differen;ated aggressive carcinoma fibroblasts and stromal cells staining – arrows highlight loss of BM and • Once crossing BM cells are malignant stromal/carcinoma interac;on Intravasaon • Aher invasion through BM and stromal cells, cancer cells enter by remodeling endothelial lining of blood vessel – between or through cells • Primary cancer cells entering the blood (or • Proteases degrade cadherin and gap junc;ons lymph) system is Intravasaon. inducing cell retrac;on Crossing the endothelial barrier during metastasis Nicolas Reymond, Bárbara Borda d'Água & Anne J. Ridley • Ac;n contrac;on is s;mulated by MLC Kinase and Nature Reviews Cancer 13, 858–870 (2013) doi:10.1038/nrc3628 calcium calmodulin signaling 2 4/20/15 Rough Travels Time to leave - Extravasaon • Several mechanisms – different than leuKocytes (can travel between endothelial cells by a process called diapedesis) – Use a similar mechanism as intravasaon • LacK of contact (many tumor cells maintain some requirement), – Can proliferate to obliterate adjacent vessel wall. loss of stromal cell factors, sheer factors and size of vessels – Helped by macrophages recruited while reroute (cancer cells > 20µM while capillaries ~3-8µM) create hos;le environment for most escaping tumor cells Trapped cells (cancer and • Most cells die by anoiKis (form of apoptosis) platelets) form microthrombus. Protease • Circulang tumor cells ohen become trapped in lungs – but and mechanical reduc;on many do not stay as they find through to ;ssue capillaries or of endothelial cells leave move within ;ssues capillary BM to invade. • Complicang passage is many tumor cells recruit and - Proliferaon within the lumen allows invasion into macrophages/platelets – found as mul;cellular aggregate surrounding parenchyma ssue • Cancer cell interac;on with platelets protect tumor cells against • Receptor mediated aachment of cancer cell to endothelial cells immune lysis by natural/hunter Killer cells. induce small G proteins (Ras, Rac, Rho) to re-arrange cancer cell shape and allow protrusion and tail retrac;on • Platelets secrete factors and help recruit neutrophils which secrete pro-inflammatory cytoKines and help adhesion. • Receptors also induce expression and secre;on of factors (integrin) and proteases to allow for junc;on disassembly of endothelial cells. • Cancer cells help the process by release of cytoKines which drive endothelial retrac;on and extravasaon by VEGEF and other factors Epithelial-Mesenchyme TransiAon (EMT) is part of maturaon as cancer cells begin before/ during intravasaon Driving Miss Daisy • Epithelial cells are highly aached to neighboring cells (via gap junc;ons and E • Cancer genomes are typically altered at mul;ple cadherin) and are poorly mo;le. Shih from points (hundreds) in a single tumor epithelial to fibroblast appearance and • Key somac mutaons which significantly contribute acquire many new mesenchymal phenotypes to tumor progression are “Driver Mutaons” Confer growth advantage and posi;ve selec;on in microenvironment • “Passenger or Neutral Mutaons” may not help tumor formaon and progression and are simply carried along and the result of mutaonal environment (lacK of repair…) • EMT Drivers include transcrip;on factors altering E- cadherin. (Snail, Slug, Zeb1 and Twist) and E cadherin itself 3 4/20/15 • E Cadherin binds and signals in epithelial cells E and N Cadherin • Tethered to ac;n E Cadherin provides tensile PancreaAc Cancer - EMT strength to cell sheets and signal via Wnt • Methylaon and point mutaon of EC drives EMT • N Cadherin increases stromal/cancer cell interac;on and inhibits sheets of cells • Bonds between NC are weaker than EC favoring mo;lity and mesenchyme liKe behavior 4 4/20/15 Stromal Cell impact and EMT-MET ColonizaAon – the new begining • Micrometastases – colonizaon by small clumps of metastasizing cancer (and associated) cells Post extravasaon EMT is reversed and • Most foreign ;ssues do not contain proper mix of colon tumor cells stromal cells/signaling factors for con;nued begin to revert to epithelial cells proliferaon resembling primary • > 30% of breast cancer paents harbor 100-1000s tumors of micrometastases but only half will show Much is driven by development of theses metastac nascent change in stromal tumors cell support 9 between original • In mice primary tumors (1g ~10 cells) seed more and distal site than 1 mil cells per day into blood/lymph but less than 5 will survive to form metastasis. • Genec heterogenaity of Proteases and Invasion/Metastasis tumors may help evolu;on of micrometastasis – Only those cells that can colonize will form secondary tumors – Evoluon of such tumors are the reason for clinical relapse from “cancer-free” paents years later 5 .
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