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Enhanced Growth and Metastasis of Colon Cancer: Role of Mesenchymal Stem Cells

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Stem Cells and Cancer Stem Cells, Volume 4

Part of the book series: Stem Cells and Cancer Stem Cells ((STEM,volume 4))

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Abstract

Carcinoma-associated fibroblasts (CAFs) contribute to cancer progression, but their precise origin and role are unclear. Several studies have shown that bone marrow-derived mesenchymal stem cells (MSCs) migrate to tumor stroma and differentiate into CAFs in the specific tumor microenvironment. However, the actual role played by MSCs and the mechanisms underlying MSC-tumor interaction are only superficially understood. We recently studied the role of human MSCs in tumor stroma using an orthotopic nude mouse model of colon cancer. Circulating MSCs migrated not only to the stroma of primary colon tumors but also to metastatic liver tumors. Orthotopic transplantation of colon cancer cells mixed with MSCs, in comparison to transplantation of cancer cells alone, resulted in greater tumor weight and a greater number of liver metastases. Moreover, tumors resulting from transplantation of mixed cells had significantly higher cell proliferative and angiogenic activities as well as significantly fewer apoptotic tumor cells. Mesenchymal stem cells incorporated into the stroma of primary and metastatic tumors expressed CAF markers α-smooth muscle actin and platelet-derived growth factor receptor-β. Thus, MSCs migrate and differentiate into CAFs in tumor stroma, where they promote growth and metastasis of colon cancer by enhancing angiogenesis, migration, and invasion and by inhibiting apoptosis of tumor cells. Blockade of the tumor-MSC interaction may abrogate colon cancer progression.

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References

  • Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H, Porter D, Hu M, Chin L, Richardson A, Schnitt S, Sellers WR, Polyak K (2004) Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 6:17–32

    Article  PubMed  CAS  Google Scholar 

  • Anderberg C, Pietras K (2009) On the origin of cancer-associated fibroblasts. Cell Cycle 8:1461–1462

    Article  PubMed  CAS  Google Scholar 

  • Beckermann BM, Kallifatidis G, Groth A, Frommhold D, Apel A, Mattern J, Salnikov AV, Moldenhauer G, Wagner W, Diehlmann A, Saffrich R, Schubert M, Ho AD, Giese N, Buchler MW, Friess H, Buchler P, Herr I (2008) VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma. Br J Cancer 99:622–631

    Article  PubMed  CAS  Google Scholar 

  • De Luca A, Gallo M, Aldinucci D, Ribatti D, Lamura L, D’Alessio A, De Filippi R, Pinto A, Normanno N (2011) The role of the EGFR ligand/receptor system in the secretion of angiogenic factors in mesenchymal stem cells. J Cell Physiol 226:2131–2138

    Article  PubMed  Google Scholar 

  • De Wever O, Mareel M (2003) Role of tissue stroma in cancer cell invasion. J Pathol 200:429–447

    Article  PubMed  Google Scholar 

  • Direkze NC, Hodivala-Dilke K, Jeffery R, Hunt T, Poulsom R, Oukrif D, Alison MR, Wright NA (2004) Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res 64:8492–8495

    Article  PubMed  CAS  Google Scholar 

  • Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315:1650–1659

    Article  PubMed  CAS  Google Scholar 

  • Dwyer RM, Potter-Beirne SM, Harrington KA, Lowery AJ, Hennessy E, Murphy JM, Barry FP, O’Brien T, Kerin MJ (2007) Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells. Clin Cancer Res 13:5020–5027

    Article  PubMed  CAS  Google Scholar 

  • Fidler IJ (1990) Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res 50:6130–6138

    PubMed  CAS  Google Scholar 

  • Fox JM, Chamberlain G, Ashton BA, Middleton J (2007) Recent advances into the understanding of mesenchymal stem cell trafficking. Br J Haematol 137:491–502

    Article  PubMed  CAS  Google Scholar 

  • Goldstein RH, Reagan MR, Anderson K, Kaplan DL, Rosenblatt M (2010) Human bone marrow-derived MSCs can home to orthotopic breast cancer tumors and promote bone metastasis. Cancer Res 70:10044–10050

    Article  PubMed  CAS  Google Scholar 

  • Hurst DR, Welch DR (2007) A MSC-ing link in metastasis? Nat Med 13:1289–1291

    Article  PubMed  CAS  Google Scholar 

  • Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249

    Article  PubMed  Google Scholar 

  • Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401

    Article  PubMed  CAS  Google Scholar 

  • Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449:557–563

    Article  PubMed  CAS  Google Scholar 

  • Kitadai Y, Bucana CD, Ellis LM, Anzai H, Tahara E, Fidler IJ (1995) In situ mRNA hybridization technique for analysis of metastasis-related genes in human colon carcinoma cells. Am J Pathol 147:1238–1247

    PubMed  CAS  Google Scholar 

  • Kitadai Y, Sasaki T, Kuwai T, Nakamura T, Bucana CD, Fidler IJ (2006a) Targeting the expression of platelet-derived growth factor receptor by reactive stroma inhibits growth and metastasis of human colon carcinoma. Am J Pathol 169:2054–2065

    Article  PubMed  CAS  Google Scholar 

  • Kitadai Y, Sasaki T, Kuwai T, Nakamura T, Bucana CD, Hamilton SR, Fidler IJ (2006b) Expression of activated platelet-derived growth factor receptor in stromal cells of human colon carcinomas is associated with metastatic potential. Int J Cancer 119:2567–2574

    Article  PubMed  CAS  Google Scholar 

  • Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT (2010) Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 330:827–830

    Article  PubMed  CAS  Google Scholar 

  • Lazennec G, Jorgensen C (2008) Concise review: adult multipotent stromal cells and cancer: risk or benefit? Stem Cells 26:1387–1394

    Article  PubMed  CAS  Google Scholar 

  • Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444

    Article  PubMed  CAS  Google Scholar 

  • Matsumoto T, Kuroda R, Mifune Y, Kawamoto A, Shoji T, Miwa M, Asahara T, Kurosaka M (2008) Circulating endothelial/skeletal progenitor cells for bone regeneration and healing. Bone 43:434–439

    Article  PubMed  CAS  Google Scholar 

  • Menon LG, Picinich S, Koneru R, Gao H, Lin SY, Koneru M, Mayer-Kuckuk P, Glod J, Banerjee D (2007) Differential gene expression associated with migration of mesenchymal stem cells to conditioned medium from tumor cells or bone marrow cells. Stem Cells 25:520–528

    Article  PubMed  CAS  Google Scholar 

  • Mishra PJ, Humeniuk R, Medina DJ, Alexe G, Mesirov JP, Ganesan S, Glod JW, Banerjee D (2008) Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer Res 68:4331–4339

    Article  PubMed  CAS  Google Scholar 

  • Mishra PJ, Glod JW, Banerjee D (2009) Mesenchymal stem cells: flip side of the coin. Cancer Res 69:1255–1258

    Article  PubMed  CAS  Google Scholar 

  • Mueller MM, Fusenig NE (2004) Friends or foes – bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4:839–849

    Article  PubMed  CAS  Google Scholar 

  • Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121:335–348

    Article  PubMed  CAS  Google Scholar 

  • Paget S (1989) The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 8:98–101

    PubMed  CAS  Google Scholar 

  • Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147

    Article  PubMed  CAS  Google Scholar 

  • Psaila B, Lyden D (2009) The metastatic niche: adapting the foreign soil. Nat Rev Cancer 9:285–293

    Article  PubMed  CAS  Google Scholar 

  • Quante M, Tu SP, Tomita H, Gonda T, Wang SS, Takashi S, Baik GH, Shibata W, Diprete B, Betz KS, Friedman R, Varro A, Tycko B, Wang TC (2011) Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 19:257–272

    Article  PubMed  CAS  Google Scholar 

  • Scott AM, Wiseman G, Welt S, Adjei A, Lee FT, Hopkins W, Divgi CR, Hanson LH, Mitchell P, Gansen DN, Larson SM, Ingle JN, Hoffman EW, Tanswell P, Ritter G, Cohen LS, Bette P, Arvay L, Amelsberg A, Vlock D, Rettig WJ, Old LJ (2003) A Phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin Cancer Res 9:1639–1647

    PubMed  CAS  Google Scholar 

  • Shinagawa K, Kitadai Y, Tanaka M, Sumida T, Kodama M, Higashi Y, Tanaka S, Yasui W, Chayama K (2010) Mesenchymal stem cells enhance growth and metastasis of colon cancer. Int J Cancer 127:2323–2333

    Article  PubMed  CAS  Google Scholar 

  • Studeny M, Marini FC, Champlin RE, Zompetta C, Fidler IJ, Andreeff M (2002) Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res 62:3603–3608

    PubMed  CAS  Google Scholar 

  • Studeny M, Marini FC, Dembinski JL, Zompetta C, Cabreira-Hansen M, Bekele BN, Champlin RE, Andreeff M (2004) Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst 96:1593–1603

    Article  PubMed  CAS  Google Scholar 

  • Sumida T, Kitadai Y, Shinagawa K, Tanaka M, Kodama M, Ohnishi M, Ohara E, Tanaka S, Yasui W, Chayama K (2011) Anti-stromal therapy with imatinib inhibits growth and metastasis of gastric carcinoma in an orthotopic nude mouse model. Int J Cancer 128:2050–2062

    Article  PubMed  CAS  Google Scholar 

  • van der Horst EH, Chinn L, Wang M, Velilla T, Tran H, Madrona Y, Lam A, Ji M, Hoey TC, Sato AK (2009) Discovery of fully human anti-MET monoclonal antibodies with antitumor activity against colon cancer tumor models in vivo. Neoplasia 11:355–364

    PubMed  Google Scholar 

  • Whiteside TL (2008) The tumor microenvironment and its role in promoting tumor growth. Oncogene 27:5904–5912

    Article  PubMed  CAS  Google Scholar 

  • Worthley DL, Ruszkiewicz A, Davies R, Moore S, Nivison-Smith I, Bik To L, Browett P, Western R, Durrant S, So J, Young GP, Mullighan CG, Bardy PG, Michael MZ (2009) Human gastrointestinal neoplasia-associated myofibroblasts can develop from bone marrow-derived cells following allogeneic stem cell transplantation. Stem Cells 27:1463–1468

    Article  PubMed  CAS  Google Scholar 

  • Zeisberg EM, Potenta S, Xie L, Zeisberg M, Kalluri R (2007) Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res 67:10123–10128

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine and Molecular Science, Hiroshima University, Graduate School of Biomedical Sciences, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Yasuhiko Kitadai & Kei Shinagawa

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  1. Yasuhiko Kitadai
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  2. Kei Shinagawa
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Correspondence to Yasuhiko Kitadai .

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  1. , Kean University, Room 213, Library building, Morris Avenue 1000, Union, 07083, New Jersey, USA

    M.A. Hayat

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Kitadai, Y., Shinagawa, K. (2012). Enhanced Growth and Metastasis of Colon Cancer: Role of Mesenchymal Stem Cells. In: Hayat, M. (eds) Stem Cells and Cancer Stem Cells, Volume 4. Stem Cells and Cancer Stem Cells, vol 4. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2828-8_23

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