DOCSLIB.ORG

Counterbalancing Angiogenic Regulatory Factors Control the Rate of Cancer Progression and Survival in a Stage-Specific Manner

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Counterbalancing Angiogenic Regulatory Factors Control the Rate of Cancer Progression and Survival in a Stage-Specific Manner Counterbalancing angiogenic regulatory factors control the rate of cancer progression and survival in a stage-specific manner Liang Xiea,1, Michael B. Duncana,1,2, Jessica Pahlerb, Hikaru Sugimotoa, Margot Martinoa, Julie Livelya,3, Thomas Mundela, Mary Soubasakosa, Kristofer Rubinc,d, Takaaki Takedae, Masahiro Inouee, Jack Lawlerf, Richard O. Hynesd, Douglas Hanahanb,4,5, and Raghu Kalluria,g,h,5 aDivision of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215; bDiabetes and Comprehensive Cancer Centers, University of California, San Francisco, CA 94143; cDepartment of Medical Biochemistry and Microbiology, Uppsala University, 75105 Uppsala, Sweden; eDepartment of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan; fDivision of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215; dHoward Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139; gDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215; and hHarvard–MIT Division of Health Sciences and Technology, Boston, MA 02215 Contributed by Douglas Hanahan, April 15, 2011 (sent for review November 12, 2010) Whereas the roles of proangiogenic factors in carcinogenesis are thelial cells (13). Thrombospondin-1 (TSP1) offers another ex- well established, those of endogenous angiogenesis inhibitors ample of how glycoproteins within the tumor microenvironment (EAIs) remain to be fully elaborated. We investigated the roles can serve as important functional regulators of angiogenesis (14). of three EAIs during de novo tumorigenesis to further test the In this study, we present genetic and pharmacological data, angiogenic balance hypothesis, which suggests that blood vessel which demonstrate that endogenous protein fragments are in- development in the tumor microenvironment can be governed by volved in regulating the angiogenic switch and controlling de a net loss of negative regulators of angiogenesis in addition to the novo tumor growth and survival associated with pancreatic well-established principle of up-regulated angiogenesis inducers. neuroendocrine tumorigenesis (PNET) in RIP-Tag2 (RT2) In a mouse model of pancreatic neuroendocrine cancer, adminis- mice. Genetic testing in a second cancer model, involving de- − − tration of endostatin, thrombospondin-1, and tumstatin peptides, letion of tumstatin and TSP1 in p53 / mice, generalizes the as well as deletion of their genes, reveal neoplastic stage-specific significance of these endogenous angiogenesis inhibitors in con- effects on angiogenesis, tumor progression, and survival, corre- trolling cancer progression and increasing overall survival. lating with endothelial expression of their receptors. Deletion of tumstatin and thrombospondin-1 in mice lacking the p53 tumor Results suppressor gene leads to increased incidence and reduced latency We documented the importance of VEGF-A gene expression for of angiogenic lymphomas associated with diminished overall the initial angiogenic switch, as illustrated in Fig. S1, assessing survival. The results demonstrate that EAIs are part of a balance hyperproliferative islets in RT2 mice in which the VEGF-A gene mechanism regulating tumor angiogenesis, serving as intrinsic had been specifically deleted within the oncogene-expressing microenvironmental barriers to tumorigenesis. islet β cells of the pancreas (RT2/VEGFRIPKO). When hyper- proliferative islet lesions (hyperplasias and dysplasias) were integrins | cell biology identified in the pancreas by BrdU labeling, both nonangiogenic islets as well as angiogenic islets were detected in VEGF wild- ngiogenesis, the formation of new blood vessels, is crucial type mice (RT2/VEGFWT), whereas the RT2/VEGFRIPKO mice Aduring transient physiological and pathological processes in had only hyperproliferative lesions without evident angiogenesis. MEDICAL SCIENCES the adult. An increasing body of evidence supports the hypoth- Hypoxia was prevalent in RT2/VEGFRIPKO islets (Fig. S1F). esis that angiogenesis is switched on and orchestrated by balance Although these results illustrate the importance of VEGF as an in the local abundance of endogenous proangiogenic and anti- inducing signal for triggering the initial angiogenic switch, the angiogenic factors (1, 2). Proangiogenic signaling is well un- data do not implicate a balance mechanism. A question remained derstood, in terms of intracellular networks and mechanistic as to whether there were significant negative regulatory signals effects (3, 4). By contrast, understanding of the roles, regulation, and effects of the counterbalancing endogenous antiangiogenic signals in regulating the angiogenic switch has lagged, due to Author contributions: R.O.H., D.H., and R.K. designed research; L.X., M.B.D., J.P., H.S., complexities in their molecular structures and receptors (5–7). M.M., J. Lively, T.M., M.S., K.R., T.T., and M.I. performed research; M.I., J. Lawler, R.O.H., Several endogenous antiangiogenic factors are proteolytic frag- D.H., and R.K. contributed new reagents/analytic tools; L.X., M.B.D., J.P., H.S., T.M., M.S., K.R., T.T., M.I., D.H., and R.K. analyzed data; and L.X., M.B.D., R.O.H., D.H., and R.K. wrote ments of structural proteins, including constituents of the vas- the paper. cular basement membrane (8). Most have several receptors or The authors declare no conflict of interest. coreceptors, in several cases including heterodimeric integrins Freely available online through the PNAS open access option. involved in anchoring endothelial cells to the vascular basement 1 membrane (9, 10). L.X. and M.B.D. contributed equally to this work. 2 Among the growing list of endogenous angiogenesis inhibitors, Present address: Section of Gastroenterology/Hepatology, Department of Medicine, Medical College of Georgia, Augusta, GA 30912. several of the best characterized are peptide fragments of natu- 3Present address: Department of Biology, Sewanee, The University of the South, Sewanee, rally occurring extracellular matrix (ECM) and basement mem- TN 37383. brane proteins (1). Endostatin, derived from the noncollagenous 4 α Present addresses: Swiss Institute for Experimental Cancer Research (ISREC) and Swiss (NC1) domain of the 1 chain of type XVIII collagen, attenuates Federal Institute of Technology Lausanne (EPFL), CH-1015 Lausanne, Switzerland. angiogenesis, tumor growth, and metastasis in experimental ani- 5To whom correspondence may be addressed. E-mail: [email protected] or mal models (11, 12). Another such fragment, tumstatin, consisting dh@epfl.ch. α of the NC1 domain of the 3 chain of type IV collagen, is anti- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. angiogenic and selectively proapoptotic to proliferating endo- 1073/pnas.1105041108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1105041108 PNAS | June 14, 2011 | vol. 108 | no. 24 | 9939–9944 Downloaded by guest on October 1, 2021 counterbalancing the proangiogenic signals exemplified by VEGF, slightly increased in the angiogenic islets, albeit without statisti- defining a balance mechanism for the initial angiogenic switch. cal significance (Fig. S2 A and D). β3 integrin was barely de- tectable in normal islets or in the premalignant stages of cancer Endostatin, Tumstatin, and TSP1 Restrict Tumor Angiogenesis and progression and then appeared robustly on most blood vessels of Growth in RT2 Mice. We used functionally active peptides derived nascent solid tumors. However, as tumors became larger, ex- from tumstatin and endostatin and a recombinant protein that pression levels decreased somewhat (Fig. S2 B and D). Coloc- includes the second type 1 repeat (TSR) of thrombospondin-1 alization of CD36 and CD31 by immunostaining revealed CD36 (TSP1), to probe the capabilities of the three endogenous in- expression in endothelial cells of normal islets and all stages of hibitors to suppress angiogenesis and tumor growth via phar- tumorigenesis (Fig. S2C). macological elevation of their levels in the circulatory system The mRNA levels of αV, β3, α5, and β1 integrin subunits along (15–17). To confirm the relative efficacy of these reagents, we with CD36 were then analyzed by quantitative real-time PCR of evaluated a 10-μM dose of each reagent (based on previous RNA prepared from physically isolated normal pancreatic islets, studies and chosen to ensure maximal activity while retaining hyperplastic/dysplastic islets, angiogenic islets, and tumors. The solubility) in cell-culture–based endothelial viability assays (15– expression of the integrin subunits increased in the tumors, 17). As shown in Fig. 1A,10μM of each peptide or recombinant compared with normal islets, by 50% to over 100%, in relation to protein reagent significantly inhibited endothelial cell viability baseline CD31 coexpression in the normal islets (Fig. S3). CD36 with similar efficacy. showed a modest decrease in gene expression in the tumor set- The endostatin, tumstatin, and TSR inhibitors were adminis- ting relative to CD31 expression. tered to RT2 mice in two trials to assess their efficacy during different stages of PNET tumorigenesis (18). A prevention trial Deficiency of Endogenous Angiogenesis Inhibitors Accelerates Islet from 5.5 to 10 wk of age was designed to assess the effect of the Carcinogenesis.
Load more

Recommended publications
  • T7 Peptide Cytotoxicity in Human Hepatocellular Carcinoma Cells Is Mediated by Suppression of Autophagy
    INTERNATIONAL JOURNAL OF MOleCular meDICine 44: 523-534, 2019 T7 peptide cytotoxicity in human hepatocellular carcinoma cells is mediated by suppression of autophagy FENG LIU1, FUHAI WANG1, XIAOFENG DONG2, PENG XIU1, PENGFEI SUN3, ZHONGCHAO LI3, XUETAO SHI3 and JINGTAO ZHONG3 1Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014; 2Department of Hepatobiliary Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi 530021; 3Department of Hepatobiliary Surgery, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Science, Jinan, Shandong 250117, P.R. China Received December 23, 2018; Accepted June 4, 2019 DOI: 10.3892/ijmm.2019.4231 Abstract. The T7 peptide, an active fragment of full-length Introduction tumstatin [the non-collagenous 1 domain of the type IV collagen α3 chain, α3 (IV) NC1], has exhibited potential Hepatocellular carcinoma (HCC) ranks sixth among the antitumor effects in several types of cancer cells. However, common types of cancer worldwide and is the third leading the mechanism underlying its action against human cause of cancer-related mortality (1). The main risk factors of hepatocellular carcinoma (HCC) remains unclear. The HCC are cirrhosis from hepatitis virus infection (hepatitis B present study aimed to investigate the role of autophagy in or C viruses), alcohol-related liver cirrhosis, and non-alcoholic T7 peptide-induced cytotoxicity in HCC cells in vitro and steatohepatitis (2). In the past decades, therapeutic options for in vivo. The results revealed that the T7 peptide significantly HCC have considerably developed, including radiofrequency reduced cell viability and induced cell cycle arrest in HCC ablation, liver transplantation, tumor resection, transarterial cells.
    [Show full text]
  • Tumstatin Peptide, an Inhibitor of Angiogenesis, Prevents Glomerular
    Tumstatin Peptide, an Inhibitor of Angiogenesis, Prevents Glomerular Hypertrophy in the Early Stage of Diabetic Nephropathy Yoshihiko Yamamoto, Yohei Maeshima, Hiroyuki Kitayama, Shinji Kitamura, Yuki Takazawa, Hitoshi Sugiyama, Yasushi Yamasaki, and Hirofumi Makino In the early stage of diabetic nephropathy (one of the gression of diabetic nephropathy, and early alterations in major microvascular complications of diabetes) glomer- diabetic nephropathy include glomerular hyperfiltration, ular hyperfiltration and hypertrophy are observed. It is glomerular and tubular epithelial hypertrophy, and the clinically important to regulate glomerular hypertrophy development of microalbuminuria (2). These early alter- for preventing glomerulosclerosis. The number of ations are followed by the development of glomerular glomerular endothelial cells is known to be increased in basement membrane thickening, the accumulation of ex- diabetic nephropathy associated with enlarged glomer- tracellular matrix components in mesangium as well as in ular tufts, suggesting that the mechanism is similar to that of angiogenesis. Tumstatin peptide is an angiogen- the interstitium, and the increase of urinary albumin esis inhibitor derived from type IV collagen and inhibits excretion, eventually leading to glomerulosclerosis and in vivo neovascularization induced by vascular endothe- progressive loss of renal function (3,4). The involvement lial growth factor (VEGF), one of the mediators of of angiotensin II, insulin-like growth factor-1, and trans- glomerular hypertrophy in diabetic nephropathy. Here, forming growth factor (TGF)-␤1 in the development of we show the effect of tumstatin peptide in inhibiting diabetic nephropathy have been reported (5,6). Vascular alterations in early diabetic nephropathy. Glomerular endothelial growth factor (VEGF) is one of the potent hypertrophy, hyperfiltration, and albuminuria were sup- stimulators of angiogenesis with the capacity to promote pressed by tumstatin peptide (1 mg/kg) in strepto- zotocin-induced diabetic mice.
    [Show full text]
  • A Novel Protein Drug, Suprachoroidal Delivery, and Protein Sustained Release Systems for Choroidal Neovascularization
    A NOVEL PROTEIN DRUG, SUPRACHOROIDAL DELIVERY, AND PROTEIN SUSTAINED RELEASE SYSTEMS FOR CHOROIDAL NEOVASCULARIZATION by PUNEET TYAGI M. Pharm., Hamdard University, India 2003 B. Pharm, CCS University, India 1997 A thesis submitted to the Faculty of the Graduate School of the University of Colorado in partial fulfillment of the requirements for the degree of Doctor of Philosophy Pharmaceutical Sciences Program 2013 This thesis for Doctor of Philosophy degree by Puneet Tyagi has been approved for the Pharmaceutical Sciences Program by Robert I. Scheinman, Chair Uday B. Kompella, Advisor Krishna Mallela Ravi Mahalingam Jeffrey Olson Date: 12/05/13 ii Tyagi, Puneet. (Ph.D., Pharmaceutical Sciences) A Novel Protein Drug, Suprachoroidal Delivery, and Protein Sustained Release Systems for Choroidal Neovascularization Thesis directed by Professor Uday B. Kompella. ABSTRACT Ocular posterior segment diseases such as age related macular degeneration are leading causes of blindness worldwide. Identification of various new disease targets have led to the development of inhibitors of vascular endothelial growth factor such as bevacizumab, ranibizumab, and aflibercept. A critical barrier for the translation of any new promising drug intended for the posterior segment diseases is drug delivery to the back of the eye. Topical eye drop, which is the most convenient dosage form, typically does not achieve therapeutically effective drug levels in the retina. Systemic modes of administration are associated with high drug exposure to other organs, and hence, systemic toxicity. Frequent intravitreal injections can lead to retinal detachment and endophthalmitis. The objective of this research was to create a novel transferrin-tumstatin fusion protein based on an endogenous antiangiogenic tumstatin and evaluate its efficacy in vitro and in vivo and compare it to bevacizumab and tumstatin.
    [Show full text]
  • In Choroidal Endothelial Cells by the A6(IV)NC1 Collagen Fragment
    Biochemistry and Molecular Biology Inhibition of Elastin Peptide-Mediated Angiogenic Signaling Mechanism(s) in Choroidal Endothelial Cells by the a6(IV)NC1 Collagen Fragment Venugopal Gunda,1,2 Raj Kumar Verma,1,3 and Yakkanti Akul Sudhakar1,4 1Cell Signaling, Retinal & Tumor Angiogenesis Laboratory, Boys Town National Research Hospital, Omaha, Nebraska 2The Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 3Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Kingsville, Texas 4Center for Cancer & Metabolism, Cell Signaling Laboratory, Bioscience Division, Stanford Research Institute (SRI) International, Menlo Park, California Correspondence:YakkantiAkulSud- PURPOSE. The inhibitory effects and mechanism(s) of type IV collagen a-6 chain–derived hakar, Center for Cancer & Metabo- noncollagenous domain (a6[IV]NC1 or hexastatin) on elastin-derived peptide (EDP)–activated lism, Cell Signaling Laboratory, choroidal endothelial cell migration, kinase signaling, and membrane type 1 metalloprotei- Bioscience Division, SRI Interna- nase (MT1-MMP) activation are explored. tional, 333 Ravenswood Avenue, Menlo Park, CA 94025-3493; METHODS. Mouse choroidal endothelial cells (MCECs) were incubated in media with soluble [email protected]. EDPs (kappa elastin, mouse elastin, and Val-Gly-Val-Ala-Pro-Gly [VGVAPG] hexapeptide) for Submitted: August 29, 2012 different time intervals with or without a6(IV)NC1. The MCECs proliferation, migration, tube Accepted: May 22, 2013 formation, MT1-MMP expression, and angiogenic signaling were analyzed in cells subjected to EDP and a6(IV)NC1 treatments. The MCECs also were subjected to EDPs, and specific Citation: Gunda V, Verma RK, Sudha- kar YA. Inhibition of elastin peptide- inhibitors for evaluation of focal adhesion kinase (FAK) and protein kinase B (Akt) mediated angiogenic signaling mecha- phosphorylation.
    [Show full text]
  • Tumstatin Induces Apoptosis Mediated by Fas Signaling Pathway in Oral Squamous Cell Carcinoma SCC-VII Cells
    1016 ONCOLOGY LETTERS 10: 1016-1022, 2015 Tumstatin induces apoptosis mediated by Fas signaling pathway in oral squamous cell carcinoma SCC-VII cells JEON HWANG-BO*, JONG-HWA PARK* and IN SIK CHUNG Department of Genetic Engineering and Graduate School of Biotechnology, Kyung Hee University, Yongin, Gyeonggi 446-701, Republic of Korea Received August 14, 2014; Accepted May 7, 2015 DOI: 10.3892/ol.2015.3261 Abstract. Oral squamous cell carcinoma is a cancer origi- Oral cancer may also occur due to metastasis from a distant nating in the tissues lining the mouth and lips. The present site of origin or by extension from a neighboring anatomical study investigated the effects of recombinant tumstatin, an structure. Approximately 90% of oral cancer cases are anti-angiogenic agent with distinct antitumor activity, on oral squamous cell carcinomas that originate in tissues lining the squamous cell carcinoma SCC-VII cells. Apoptosis was char- mouth and lips (2). Squamous cell carcinoma is managed by acterized by YO-PRO-1 staining, sub-G1 population, and DNA surgery, radiotherapy and chemotherapy, alone or in combina- fragmentation analysis. Apoptotic mechanism of tumstatin tion; however, the five‑year survival rate is poor, at ~50% (2). was also investigated. The antitumor activity of tumstatin was Therefore, novel diagnostic and therapeutic methods to detect further evaluated using an SCC-VII animal model. Recombinant squamous cell carcinomas at an early stage and increase the tumstatin was found to decrease the viability of SCC-VII cells in survival rate are urgently required. a dose-dependent manner. The number of cells stained with the Apoptosis, a strictly controlled mechanism of cell death, apoptotic marker YO-PRO-1, the sub-G1 cell population and the is triggered by internal or external signals.
    [Show full text]
  • The Matrix Reloaded: New Insights from Type IV Collagen Derived
    Journal of Bioequivalence & Bioavailability - Open Access Expert Review JBB/Vol.1 July-August 2009 The Matrix Reloaded: New Insights from Type IV Collagen Derived Endogenous Angiogenesis Inhibitors and their Mechanism of Action Akulapalli Sudhakar1,2,3,* 1Cell Signaling and Tumor Angiogenesis Laboratory, Department of Genetics, Boys Town National Research Hospital, Omaha 2 Department of Biomedical Sciences, Creighton University School of Medicine, Omaha 3Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha *Corresponding author: Akulapalli Sudhakar, MS., M.Phill & Ph.D, Assistant Professor/Staff Scientist II, Creighton University School of Medicine and University of Nebraska Mecical Center, Director: Cell Signaling and Tumor Angiogenesis Laboratory, Boys Town National Research Hospital, 555 N, 30th Street, Omaha NE 68131, USA, Tel: (402) 498-6681, (402) 498-6322; Fax: (402) 498-6331; E-mail: [email protected] Received August 19, 2009; Accepted August 21, 2009; Published August 22, 2009 Citation: Sudhakar A (2009) The Matrix Reloaded: New Insights from Type IV Collagen Derived Endogenous Angio- genesis Inhibitors and their Mechanism of Action. J Bioequiv Availab 1: 052-062. doi:10.4172/jbb.1000009 Copyright: © 2009 Sudhakar A. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Angiogenesis, the process of neovascularization from parent blood vessels, is a prerequisite for many physiologi- cal and pathological conditions that is regulated by a balance between the levels of endogenous angiogenic stimu- lators and matrix reloaded angiogenic regulators. Several non-collagenous carboxy terminal end domains in α chains of type IV collagen matrix reloaded molecules selectively interact with proliferating endothelial cells by binding to distinct integrins and regulate intracellular signaling and inhibit angiogenesis.
    [Show full text]
  • Relapse of Pathological Angiogenesis: Functional Role of the Basement Membrane and Potential Treatment Strategies Anthony Mukwaya 1, Lasse Jensen2 and Neil Lagali 1,3
    Mukwaya et al. Experimental & Molecular Medicine (2021) 53:189–201 https://doi.org/10.1038/s12276-021-00566-2 Experimental & Molecular Medicine REVIEW ARTICLE Open Access Relapse of pathological angiogenesis: functional role of the basement membrane and potential treatment strategies Anthony Mukwaya 1, Lasse Jensen2 and Neil Lagali 1,3 Abstract Blinding eye diseases such as corneal neovascularization, proliferative diabetic retinopathy, and age-related macular degeneration are driven by pathological angiogenesis. In cancer, angiogenesis is key for tumor growth and metastasis. Current antiangiogenic treatments applied clinically interfere with the VEGF signaling pathway—the main angiogenic pathway—to inhibit angiogenesis. These treatments are, however, only partially effective in regressing new pathologic vessels, and the disease relapses following cessation of treatment. Moreover, the relapse of pathological angiogenesis can be rapid, aggressive and more difficult to treat than angiogenesis in the initial phase. The manner in which relapse occurs is poorly understood; however, recent studies have begun to shed light on the mechanisms underlying the revascularization process. Hypotheses have been generated to explain the rapid angiogenic relapse and increased resistance of relapsed disease to treatment. In this context, the present review summarizes knowledge of the various mechanisms of disease relapse gained from different experimental models of pathological angiogenesis. In addition, the basement membrane—a remnant of regressed vessels—is
    [Show full text]
  • The Role of Cysteine Cathepsins in Cancer Progression and Drug Resistance
    International Journal of Molecular Sciences Review The Role of Cysteine Cathepsins in Cancer Progression and Drug Resistance Magdalena Rudzi ´nska 1, Alessandro Parodi 1, Surinder M. Soond 1, Andrey Z. Vinarov 2, Dmitry O. Korolev 2, Andrey O. Morozov 2, Cenk Daglioglu 3 , Yusuf Tutar 4 and Andrey A. Zamyatnin Jr. 1,5,* 1 Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia 2 Institute for Urology and Reproductive Health, Sechenov University, 119992 Moscow, Russia 3 Izmir Institute of Technology, Faculty of Science, Department of Molecular Biology and Genetics, 35430 Urla/Izmir, Turkey 4 Faculty of Pharmacy, University of Health Sciences, 34668 Istanbul, Turkey 5 Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia * Correspondence: [email protected]; Tel.: +7-4956229843 Received: 26 June 2019; Accepted: 19 July 2019; Published: 23 July 2019 Abstract: Cysteine cathepsins are lysosomal enzymes belonging to the papain family. Their expression is misregulated in a wide variety of tumors, and ample data prove their involvement in cancer progression, angiogenesis, metastasis, and in the occurrence of drug resistance. However, while their overexpression is usually associated with highly aggressive tumor phenotypes, their mechanistic role in cancer progression is still to be determined to develop new therapeutic strategies. In this review, we highlight the literature related to the role of the cysteine cathepsins in cancer biology, with particular emphasis on their input into tumor biology. Keywords: cysteine cathepsins; cancer progression; drug resistance 1. Introduction Cathepsins are lysosomal proteases and, according to their active site, they can be classified into cysteine, aspartate, and serine cathepsins [1].
    [Show full text]
  • The P53 Tumor-Suppressor Gene—Inhibiting Tumor Angiogenesis
    Current Issues The p53 Tumor-suppressor Gene—Inhibiting Tumor Angiogenesis a report by Jose G Teodoro, PhD Virologist and Cancer Biologist, Goodman Cancer Center, and Assistant Professor, Department of Biochemistry, Faculty of Medicine, McGill University DOI: 10.17925/OHR.2008.04.1.15 Angiogenesis is defined as the process by which new blood vessels are Tumor Angiogenesis and p53 formed, and research investigating how this physiological process is regulated The gene encoding the p53 tumor suppressor, TP53, is mutated in half of has exploded in recent years. Targeting tumor angiogenesis has now become all human cancers, and the correlation between p53 mutation and the a well-validated approach for treating cancer, and first-generation aggression of cancers has been observed in dozens of published angiogenesis inhibitors have been approved for clinical use since 2004. The reports describing many different tumor types.2,3 Histological studies of development of effective angiogenesis inhibitors remains a high priority human tumors have provided considerable links between p53 and within the pharmaceutical community and continues to be a highly active angiogenesis. Tumors that have mutated p53 tend to be significantly avenue of new drug discovery. more vascularized as measured by microvessel density (MVD) than tumors that retain functional p53. This correlation has been observed in The therapeutic inhibition of angiogenesis is clinically feasible since in normal several types of human cancers, including prostate,4,5 colon,5,6 breast,7 physiology this process is required mainly during periods of rapid tissue and head and neck tumors.8 Collectively, these clinical observations expansion, such as development and childhood growth.
    [Show full text]
  • Differential Expression of COL4A3 and Collagen in Upward and Downward Progressing Types of Nasopharyngeal Carcinoma
    ONCOLOGY LETTERS 21: 223, 2021 Differential expression of COL4A3 and collagen in upward and downward progressing types of nasopharyngeal carcinoma XITING YANG*, QIUJI WU*, FENGYANG WU and YAHUA ZHONG Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China Received May 4, 2020; Accepted December 21, 2020 DOI: 10.3892/ol.2021.12484 Abstract. Upward (local growth and invasion of the base of type (2.161±1.306 vs. 5.077±3.619; P<0.05). In addition, the skull), downward (distant metastasis) and mixed progressing deposition of collagen in the downward progressing type was types of nasopharyngeal carcinoma (NPC) have been identified also significantly decreased compared with that in the upward and are distinctly different with respect to clinical symptoms, progressing type (5.63±6.83 vs. 10.94±9.60; P<0.05). Kaplan- therapeutic strategies and prognosis. The present study aimed Meier analysis indicated that high expression level of COL4A3 to identify the genetic difference and collagen expression was positively associated with a favorable prognosis of head levels in the upward and downward progressing types of NPC. and neck squamous cell carcinoma (HR, 0.69; 95% CI, 0.49- Whole exon sequencing (WES) was used to detect genes 0.97; P=0.031). To confirm the role ofCOL4A3 , the expression differentially mutated between the upward and downward level of COL4A3 was knocked down using siRNA in the 5-8F progressing types of NPC. Collagen deposition in the upward cell line and the results showed that the invasion and migration and downward progressing types of NPC was determined using was significantly increased when the expression of COL4A3 Masson trichromatic staining, while the protein expression was inhibited (P<0.0001).
    [Show full text]
  • Endogenous Inhibitors of Angiogenesis
    Review Endogenous Inhibitors of Angiogenesis Pia Nyberg, Liang Xie, and Raghu Kalluri Center for Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts Abstract factor, and hypoxic conditions that activate hypoxia-inducible Angiogenesis, the formation of new blood vessels, is required factor-1, which itself can up-regulate angiogenic proteins, as well as for many pathologic processes, including invasive tumor angiogenic oncogenes, such as Ras, and tumor suppressors, such as growth as well as physiologic organ/tissue maintenance. p53. Endogenous inhibitors of angiogenesis include various Angiogenesis during development and adulthood is likely antiangiogenic peptides, hormone metabolites, and apoptosis regulated by a balance between endogenous proangiogenic modulators (Fig. 2; for reviews, see refs. 1, 4). To understand how and antiangiogenic factors. It is speculated that tumor growth systemic angiogenesis balance in the body is regulated by requires disruption of such balance; thus, the angiogenic endogenous inhibitors of angiogenesis requires an understanding switch must be turned ‘‘on’’ for cancer progression. If the of how many such molecules exist and their role in inhibiting angiogenic switch needs to be turned on to facilitate the angiogenesis. This review will highlight the important features of tumor growth, the question remains as to what the physiologic each of these molecules and address their role in the regulation of status of this switch is in the adult human body; is it ‘‘off,’’ with angiogenesis balance. inhibitors outweighing the stimulators, or maintained at a Vascular basement membrane components can modulate fine ‘‘balance,’’ keeping the proangiogenic properties of many endothelial cell behavior in addition to providing structural and factors at a delicate ‘‘activity’’ balance with endogenous functional support (5).
    [Show full text]
  • Tumstatin, a Matrikine Derived from Collagen Type IVα3, Is Elevated In
    Downloaded from orbit.dtu.dk on: Oct 02, 2021 Tumstatin, a Matrikine Derived from Collagen Type IV3, is Elevated in Serum from Patients with Non-Small Cell Lung Cancer Nielsen, Signe Holm; Willumsen, Nicholas; Brix, Susanne; Sun, Shu; Manon-Jensen, Tina; Karsdal, Morten; Genovese, Federica Published in: Translational Oncology Link to article, DOI: 10.1016/j.tranon.2018.02.005 Publication date: 2018 Document Version Publisher's PDF, also known as Version of record Link back to DTU Orbit Citation (APA): Nielsen, S. H., Willumsen, N., Brix, S., Sun, S., Manon-Jensen, T., Karsdal, M., & Genovese, F. (2018). Tumstatin, a Matrikine Derived from Collagen Type IV3, is Elevated in Serum from Patients with Non-Small Cell Lung Cancer. Translational Oncology, 11(2), 528-534. https://doi.org/10.1016/j.tranon.2018.02.005 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Translational Oncology Volume 11 Number 2 April 2018 pp.
    [Show full text]