Adipocyte-derived endotrophin promotes malignant tumor progression
Open accessAbstract
Adipocytes represent a major cell type in the mammary tumor microenvironment and are important for tumor growth. Collagen VI (COL6) is highly expressed in adipose tissue, upregulated in the obese state, and enriched in breast cancer lesions and is a stimulator of mammary tumor growth. Here, we have described a cleavage product of the COL6α3 chain, endotrophin (ETP), which serves as the major mediator of the COL6-mediated tumor effects. ETP augmented fibrosis, angiogenesis, and inflammation through recruitment of macrophages and endothelial cells. Moreover, ETP expression was associated with aggressive mammary tumor growth and high metastatic growth. These effects were partially mediated through enhanced TGF-β signaling, which contributes to tissue fibrosis and epithelial-mesenchymal transition (EMT) of tumor cells. Our results highlight the crucial role of ETP as an obesity-associated factor that promotes tumor growth in the context of adipocyte interactions with tumor and stromal cells.
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Collagen VI is cleaved at the C5 domain of the α3 subunit, and the resulting peptide increases collagen deposition, endothelial cell migration, and macrophage infiltration.
“For example collagen VI is cleaved at the C5 domain of the α3 subunit and the resulting peptide induces multiple processes including increasing collagen deposition, endothelial cell migration and macrophage infiltration (46,47).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [46]
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Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590 · see citing works
Obesity is associated with macrophage accumulation in adipose tissue
Weisberg, S. P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R. L., & Ferrante, A. W. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200319246 · Cited by 10,041 · see citing works
Massagué, J. (1998) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.67.1.753 · Cited by 7,571 · see citing works
Epithelial–mesenchymal transitions in tumour progression
Thiery, J. P. (2002) · Nature reviews. Cancer · doi:10.1038/nrc822 · Cited by 6,632 · see citing works
Renehan, A. G., Tyson, M., Egger, M., Heller, R. F., & Zwahlen, M. (2008) · The Lancet · doi:10.1016/s0140-6736(08)60269-x · Cited by 5,219 · see citing works
Kalluri, R., & Zeisberg, M. (2006) · Nature Reviews Cancer · doi:10.1038/nrc1877 · Cited by 4,538 · see citing works
Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling
Levental, K. R., Yu, H., Kass, L., Lakins, J. N., Egeblad, M., Erler, J. T., Fong, S. F. T., Csiszar, K., Giaccia, A., Weninger, W., et al. (2009) · Cell · doi:10.1016/j.cell.2009.10.027 · Cited by 4,101 · see citing works
Complex networks orchestrate epithelial–mesenchymal transitions
Thiery, J. P., & Sleeman, J. P. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1835 · Cited by 3,961 · see citing works
Microenvironmental regulation of metastasis
Joyce, J. A., & Pollard, J. W. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2618 · Cited by 3,684 · see citing works
Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms
Calle, E. E., & Kaaks, R. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1408 · Cited by 3,613 · see citing works
Tumorigenesis and the angiogenic switch
Bergers, G., & Benjamin, L. E. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1093 · Cited by 3,559 · see citing works
Adipocytokines: mediators linking adipose tissue, inflammation and immunity
Tilg, H., & Moschen, A. R. (2006) · Nature reviews. Immunology · doi:10.1038/nri1937 · Cited by 3,196 · see citing works
Adipose tissue remodeling and obesity
Sun, K., Kusminski, C. M., & Scherer, P. E. (2011) · Journal of Clinical Investigation · doi:10.1172/jci45887 · Cited by 1,941 · see citing works
Self-citationGuy, C. T., Cardiff, R. D., & Muller, W. J. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.3.954 · Cited by 1,523 · see citing works
Strategies for MMP inhibition in cancer: innovations for the post-trial era
Overall, C. M., & López-Otín, C. (2002) · Nature Reviews Cancer · doi:10.1038/nrc884 · Cited by 1,349 · see citing works
Trophic macrophages in development and disease
Pollard, J. W. (2009) · Nature Reviews Immunology · doi:10.1038/nri2528 · Cited by 1,178 · see citing works
Lin, E. Y., Jones, J. G., Li, P., Zhu, L., Whitney, K. D., Muller, W. J., & Pollard, J. W. (2003) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63568-7 · Cited by 1,109 · see citing works
Scherer, P. E. (2006) · Diabetes · doi:10.2337/db06-0263 · Cited by 1,067 · see citing works
Self-citationMetabolic Dysregulation and Adipose Tissue Fibrosis: Role of Collagen VI
Khan, T., Muise, E. S., Iyengar, P., Wang, Z. V., Chandalia, M., Abate, N., Zhang, B. B., Bonaldo, P., Chua, S., & Scherer, P. E. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.01300-08 · Cited by 1,053 · see citing works
Self-citationStromal Effects on Mammary Gland Development and Breast Cancer
Wiseman, B. S., & Werb, Z. (2002) · Science · doi:10.1126/science.1067431 · Cited by 926 · see citing works
Hypoxia-Inducible Factor 1α Induces Fibrosis and Insulin Resistance in White Adipose Tissue
Halberg, N., Khan, T., Trujillo, M. E., Wernstedt-Asterholm, I., Attie, A. D., Sherwani, S., Wang, Z. V., Landskroner-Eiger, S., Dineen, S., Magalang, U. J., et al. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00192-09 · Cited by 896 · see citing works
Self-citationHeterotypic Signaling between Epithelial Tumor Cells and Fibroblasts in Carcinoma Formation
Elenbaas, B., & Weinberg, R. A. (2001) · Experimental Cell Research · doi:10.1006/excr.2000.5133 · Cited by 557 · see citing works
Spencer, M., Yao-Borengasser, A., Unal, R., Rasouli, N., Gurley, C. M., Zhu, B., Peterson, C. A., & Kern, P. A. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00329.2010 · Cited by 439 · see citing works
Iyengar, P., Espina, V. A., Williams, T. W., Lin, Y., Berry, D. C., Jelicks, L. A., Lee, H., Temple, K. A., Graves, R., Pollard, J. W., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23424 · Cited by 429 · see citing works
Self-citationGinsberg, M. H., Partridge, A. W., & Shattil, S. J. (2005) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2005.08.010 · Cited by 415 · see citing works
Signaling Pathways in Mammary Gland Development
Hennighausen, L. G., & Robinson, G. W. (2001) · Developmental Cell · doi:10.1016/s1534-5807(01)00064-8 · Cited by 414 · see citing works
Iyengar, P., Combs, T. P., Shah, S. J., Gouon–Evans, V., Pollard, J. W., Albanese, C., Flanagan, L., Tenniswood, M., Guha, C., Lisanti, M. P., et al. (2003) · Oncogene · doi:10.1038/sj.onc.1206737 · Cited by 364 · see citing works
Self-citationParacrine and Endocrine Effects of Adipose Tissue on Cancer Development and Progression
Park, J., Euhus, D., & Scherer, P. E. (2011) · Endocrine Reviews · doi:10.1210/er.2010-0030 · Cited by 349 · see citing works
Self-citationAdipose Tissue Collagen VI in Obesity
Pasarica, M., Gawrońska‐Kozak, B., Burk, D. H., Remedios, I., Hymel, D., Gimble, J., Ravussin, É., Bray, G. A., & Smith, S. R. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0947 · Cited by 338 · see citing works
Mapping normal and cancer cell signalling networks: towards single-cell proteomics
Irish, J. M., Kotecha, N., & Nolan, G. P. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1804 · Cited by 315 · see citing works
Bonaldo, P. (1998) · Human Molecular Genetics · doi:10.1093/hmg/7.13.2135 · Cited by 306 · see citing works
Maquoi, E., Munaut, C., Colige, A., Collen, D., & Lijnen, H. R. (2002) · Diabetes · doi:10.2337/diabetes.51.4.1093 · Cited by 271 · see citing works
Forrester, E., Chytil, A., Bierie, B., Aakre, M. E., Gorska, A. E., Sharif‐Afshar, A., Muller, W. J., & Moses, H. L. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-3272 · Cited by 248 · see citing works
TEM8 Interacts with the Cleaved C5 Domain of Collagen α3(VI)
Nanda, A., Carson-Walter, E. B., Seaman, S., et al. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-2408 · Cited by 213 · see citing works
Veidal, S. S., Karsdal, M. A., Vassiliadis, E., Nawrocki, A., Larsen, M. R., Nguyen, Q. H. T., Hägglund, P., Luo, Y., Zheng, Q., Vainer, B., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0024753 · Cited by 177 · see citing works
Naugle, J. E., Olson, E. R., Zhang, X., Mase, S. E., Pilati, C. F., Maron, M. B., Folkesson, H. G., Horne, W. I., Doane, K. J., & Meszaros, J. G. (2005) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00321.2005 · Cited by 171 · see citing works
Muraoka-Cook, R. S., Kurokawa, H., Koh, Y., Forbes, J. T., Roebuck, L. R., Barcellos‐Hoff, M. H., Moody, S. E., Chodosh, L. A., & Arteaga, C. L. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-2111 · Cited by 159 · see citing works
Cloning of cell-specific secreted and surface proteins by subtractive antibody screening
Scherer, P. E., Bickel, P. E., Kotler, M., & Lodish, H. F. (1998) · Nature Biotechnology · doi:10.1038/nbt0698-581 · Cited by 144 · see citing works
Self-citationMuraoka-Cook, R. S., Shin, I., Yi, J. Y., Easterly, E., Barcellos‐Hoff, M. H., Yingling, J. M., Zent, R., & Arteaga, C. L. (2005) · Oncogene · doi:10.1038/sj.onc.1208964 · Cited by 137 · see citing works
Motrescu, E. R., Blaise, S. A., Etique, N., et al. (2008) · Oncogene · doi:10.1038/onc.2008.218 · Cited by 125 · see citing works
Increased Expression of Type VI Collagen in Lung Fibrosis
Specks, U., Nerlich, M. L., Colby, T. V., et al. (1995) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/ajrccm.151.6.7767545 · Cited by 117 · see citing works
The Supramolecular Organization of Collagen VI Microfibrils
Baldock, C., Sherratt, M. J., Shuttleworth, C. A., & Kielty, C. M. (2003) · Journal of Molecular Biology · doi:10.1016/s0022-2836(03)00585-0 · Cited by 111 · see citing works
Lai, K. K. Y., Shang, S., Lohia, N., Booth, G. C., Masse, D. J., Fausto, N., Campbell, J. S., & Beretta, L. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002147 · Cited by 101 · see citing works
The C5 Domain of Col6A3 Is Cleaved Off from the Col6 Fibrils Immediately after Secretion
Aigner, T. G., Hambach, L., Söder, S., Schlötzer-Schrehardt, U. M., & Pöschl, E. (2002) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2001.6227 · Cited by 89 · see citing works
Collagen VI Regulates Normal and Transformed Mesenchymal Cell Proliferationin Vitro
Atkinson, J. C., Rühl, M., Becker, J. C., et al. (1996) · Experimental Cell Research · doi:10.1006/excr.1996.0328 · Cited by 87 · see citing works
Lamandé, S. R., Mörgelin, M., Adams, N. E., Selan, C., & Allen, J. M. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m510192200 · Cited by 81 · see citing works
Tumor-specific expression and alternative splicing of the COL6A3 gene in pancreatic cancer
Arafat, H. A., Lazar, M. A., Salem, K., Chipitsyna, G. I., Gong, Q., Pan, T., Zhang, R.-Z., Yeo, C. J., & Chu, M. (2011) · Surgery · doi:10.1016/j.surg.2011.05.011 · Cited by 80 · see citing works
Park, J., Kusminski, C. M., Chua, S. C., & Scherer, P. E. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.100595 · Cited by 80 · see citing works
Self-citationImmunohistochemical localization of collagen VI in arthrofibrosis
Zeichen, J., van Griensven, M., Albers, I., Lobenhoffer, P. P., & Bösch, U. (1999) · Archives of Orthopaedic and Trauma Surgery · doi:10.1007/s004020050417 · Cited by 49 · see citing works
Prediction of Liver Fibrosis According to Serum Collagen VI Level in Children with Cystic Fibrosis
Gerling, B., Becker, M., Staab, D., et al. (1997) · New England Journal of Medicine · doi:10.1056/nejm199705293362217 · Cited by 45 · see citing works
Smith, M. J. F., Culhane, A. C., Donovan, M. D., Coffey, J. C., Barry, B. D., Kelly, M. A., Higgins, D. G., Wang, J., Kirwan, W. O., Cotter, T. G., et al. (2009) · British Journal of Cancer · doi:10.1038/sj.bjc.6604931 · Cited by 39 · see citing works
Collagen VI in the extracellular matrix of normal and failing human myocardium.
Mollnau, H., Münkel, B., & Schaper, J. (1995) · PubMed · Cited by 23 · see citing works
Flagged first, then by citations
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- [27]Massague J. TGF-beta signal transduction. Annu Rev Biochem . 1998;67:753-791.
Cited by
Sorted by citations
Fibrosis and adipose tissue dysfunction.
Sun, K., Tordjman, J., Clément, K., & Scherer, P. E. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.06.016 · Cited by 960 · see citing works
Self-citationThe ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis.
Crewe, C., An, Y. A., & Scherer, P. E. (2017) · Journal of Clinical Investigation · doi:10.1172/jci88883 · Cited by 732 · see citing works
Self-citationTargeting adipose tissue in the treatment of obesity-associated diabetes
Kusminski, C. M., Bickel, P. E., & Scherer, P. E. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.75 · Cited by 678 · see citing works
Self-citationBochet, L., Lehuédé, C., Dauvillier, S., Wang, Y. Y., Dirat, B., Laurent, V., Dray, C., Guiet, R., Maridonneau-Parini, I., Le Gonidec, S., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-0530 · Cited by 529 · see citing works
The good and the bad collagens of fibrosis – Their role in signaling and organ function
Karsdal, M. A., Nielsen, S. H., Leeming, D. J., Langholm, L. L., Nielsen, M. J., Manon-Jensen, T., Siebuhr, A., Gudmann, N. S., Rønnow, S., Sand, J. M., et al. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.07.014 · Cited by 509 · see citing works
Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction
Sun, K., Park, J., Gupta, O. T., Holland, W. L., Auerbach, P., Zhang, N., Goncalves Marangoni, R., Nicoloro, S. M., Czech, M. P., Varga, J., et al. (2014) · Nature Communications · doi:10.1038/ncomms4485 · Cited by 364 · see citing works
Self-citationMatricryptins and matrikines: biologically active fragments of the extracellular matrix
Ricard‐Blum, S., & Salza, R. (2014) · Experimental Dermatology · doi:10.1111/exd.12435 · Cited by 224 · see citing works
Collagen biology and non‐invasive biomarkers of liver fibrosis
Karsdal, M. A., Daniels, S. J., Holm Nielsen, S., Bager, C., Rasmussen, D. G. K., Loomba, R., Surabattula, R., Villesen, I. F., Luo, Y., Shevell, D., et al. (2020) · Liver International · doi:10.1111/liv.14390 · Cited by 197 · see citing works
Contribution of adipose tissue to development of cancer
Cozzo, A. J., Fuller, A. M., & Makowski, L. (2017) · Comprehensive Physiology · doi:10.1002/cphy.c170008 · Cited by 188 · see citing works
Scherer, P. E. (2016) · Diabetes · doi:10.2337/db16-0339 · Cited by 133 · see citing works
“Additional molecules, such as resistin (25,26), fibroblast growth factor 21 (FGF21) (27), and endotrophin (28), were added to that list of adipocyte-enriched secretory products at later points by us and others (Fig.”
Self-citationLackey, D. E., Burk, D. H., Ali, M. R., Mostaedi, R., Smith, W. H., Park, J., Scherer, P. E., Seay, S. A., McCoin, C. S., Bonaldo, P., et al. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00476.2013 · Cited by 111 · see citing works
Self-citationDankel, S. N., Svärd, J., Matthä, S., Claussnitzer, M., Klöting, N., Glunk, V., Fandalyuk, Z., Grytten, E., Solsvik, M. H., Nielsen, H., et al. (2014) · Obesity · doi:10.1002/oby.20758 · Cited by 95 · see citing works
Pellegata, N. S., Berriel Diaz, M., Rohm, M., & Herzig, S. (2022) · Cancer and Metastasis Reviews · doi:10.1007/s10555-022-10058-y · Cited by 33 · see citing works
- Authors
- Park, J., & Scherer, P. E.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Scherer, Philipp E.
- Venue
- Journal of Clinical Investigation
- Published
- 2012-10-08
- Volume
- 122
- Issue
- 11
- Pages
- 4243-4256
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3484450
- OpenAlex
- W2039694476
- Cited by
- 350
- References
- 52
- Citations by year
- 2026: 14 · 2025: 19 · 2024: 22 · 2023: 29 · 2022: 38 · 2021: 36 · 2020: 53 · 2019: 21 · 2018: 21 · 2017: 20 · 2016: 25 · 2015: 11 · 2014: 16 · 2013: 20 · 2012: 4
- FWCI
- 7.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
- Funders
- National Cancer Institute (R01CA112023, U24CA126608, P30CA142543)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK 55758, DK081182, PL1DK081182, R01DK055758, P01DK088761)
- National Center for Research Resources (S10RR024757)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- endotrophin, collagen VI, adipocytes, breast cancer, tumor progression, metastasis, fibrosis, angiogenesis, macrophage recruitment, TGF-beta signaling, epithelial-mesenchymal transition, obesity, tumor stroma
- MeSH terms
- Animals, Cell Communication, Female, Fibrosis, Macrophages, Neoplasm Metastasis, Neoplasm Proteins, Neovascularization, Pathologic, Peptide Fragments, Mammary Neoplasms, Animal, Gene Expression Regulation, Neoplastic, Transforming Growth Factor beta, Stromal Cells, Adipocytes, Collagen Type VI, Endothelial Cells, Cell Line, Tumor, Mice, Epithelial-Mesenchymal Transition, Proteolysis
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