Tumor Biology

, Volume 36, Issue 8, pp 6239–6248 | Cite as

Stromal cells of endometrial carcinoma promotes proliferation of epithelial cells through the HGF/c-Met/Akt signaling pathway

Research Article

Abstract

Tumor microenvironment participates in the endometrial carcinoma pathogenesis. This study focuses on the interaction between endometrial cancer stromal cells and epithelial cells from normal endometrium tissue using in vitro transwell coculture system and in vivo xenograft model. We demonstrate that cancer interstitial (CI) cells stimulate normal epithelial (NE) cell proliferation. Tumor xenograft model confirmed the pro-proliferative effect of CI cells on epithelial cell growth. Tumor suppressor PTEN was reduced, and oncogene K-ras was increased in epithelial cells cocultured with CI cells. Moreover, we observed increased expression of hepatocyte growth factor (HGF) in CI cells and tumor xenografts derived from the coculturing system. Higher HGF secretion activated Akt signaling pathway, which was reversed by HGF receptor inhibitor (crizotinib). These results demonstrate that endometrial carcinoma stromal cells stimulate epithelial cell proliferation via the HGF/c-Met/Akt signaling pathway.

Keywords

Endometrial carcinoma Tumor microenvironment HGF Akt signaling pathway 

References

  1. 1.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.CrossRefPubMedGoogle Scholar
  2. 2.
    Amant F, Moerman P, Neven P, Timmerman D, Van Limbergen E, Vergote I. Endometrial cancer. Lancet. 2005;366:491–505.CrossRefPubMedGoogle Scholar
  3. 3.
    Peng Q, Mo C, Qin A, Lao X, Chen Z, Sui J, et al. MDM2 SNP309 polymorphism contributes to endometrial cancer susceptibility: evidence from a meta-analysis. J Exp Clin Cancer Res. 2013;32:85.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Azueta A, Gatius S, Matias-Guiu X. Endometrioid carcinoma of the endometrium: pathologic and molecular features. Semin Diagn Pathol. 2010;27:226–40.CrossRefPubMedGoogle Scholar
  5. 5.
    Ueda Y, Enomoto T, Miyatake T, Egawa-Takata T, Ugaki H, Yoshino K, et al. Endometrial carcinoma with extra-abdominal metastasis: improved prognosis following cytoreductive surgery. Ann Surg Oncol. 2010;17:1111–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Minig L, Franchi D, Boveri S, Casadio C, Bocciolone L, Sideri M. Progestin intrauterine device and GnRH analogue for uterus-sparing treatment of endometrial precancers and well-differentiated early endometrial carcinoma in young women. Ann Oncol. 2011;22:643–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Zhou Q, Lu X, Gan L, Chen S, Zhou T, Wang L, et al. Role of REG Ialpha in gastric carcinogenesis: gastrin-associated proliferative and anti-apoptotic activities. Mol Med Rep. 2010;3:999–1005.PubMedGoogle Scholar
  8. 8.
    Manoharan S, Palanimuthu D, Baskaran N, Silvan S. Modulating effect of lupeol on the expression pattern of apoptotic markers in 7, 12-dimethylbenz(a)anthracene induced oral carcinogenesis. Asian Pac J Cancer Prev. 2012;13:5753–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Ravindran A, Mohammed J, Gunderson AJ, Cui X, Glick AB. Tumor-promoting role of TGFbeta1 signaling in ultraviolet B-induced skin carcinogenesis is associated with cutaneous inflammation and lymph node migration of dermal dendritic cells. Carcinogenesis. 2014;35:959–66.CrossRefPubMedGoogle Scholar
  10. 10.
    Wu RC, Jiang M, Beaudet AL, Wu MY. ARID4A and ARID4B regulate male fertility, a functional link to the AR and RB pathways. Proc Natl Acad Sci U S A. 2013;110:4616–21.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Tlsty TD, Coussens LM. Tumor stroma and regulation of cancer development. Annu Rev Pathol. 2006;1:119–50.CrossRefPubMedGoogle Scholar
  12. 12.
    Zhang XH, Jin X, Malladi S, Zou Y, Wen YH, Brogi E, et al. Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma. Cell. 2013;154:1060–73.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Hildenbrand R, Schaaf A. The urokinase-system in tumor tissue stroma of the breast and breast cancer cell invasion. Int J Oncol. 2009;34:15–23.PubMedGoogle Scholar
  14. 14.
    Howe JR, Roth S, Ringold JC, Summers RW, Jarvinen HJ, Sistonen P, et al. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science. 1998;280:1086–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Sneddon JB, Zhen HH, Montgomery K, van de Rijn M, Tward AD, West R, et al. Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation. Proc Natl Acad Sci U S A. 2006;103:14842–7.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Lee C, Jia Z, Rahmatpanah F, Zhang Q, Zi X, McClelland M, et al. Role of the adjacent stroma cells in prostate cancer development and progression: synergy between TGF-beta and IGF signaling. Biomed Res Int. 2014;2014:502093.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Am J Obstet Gynecol. 1975;122:262–3.CrossRefPubMedGoogle Scholar
  18. 18.
    Subramaniam KS, Tham ST, Mohamed Z, Woo YL, Mat AN, Chung I. Cancer-associated fibroblasts promote proliferation of endometrial cancer cells. PLoS One. 2013;8:e68923.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Shi M, Zhang H, Li M, Xue J, Fu Y, Yan L, et al. Normal endometrial stromal cells regulate survival and apoptosis signaling through PI3K/AKt/Survivin pathway in endometrial adenocarcinoma cells in vitro. Gynecol Oncol. 2011;123:387–92.CrossRefPubMedGoogle Scholar
  20. 20.
    Castelbaum AJ, Ying L, Somkuti SG, Sun J, Ilesanmi AO, Lessey BA. Characterization of integrin expression in a well differentiated endometrial adenocarcinoma cell line (Ishikawa). J Clin Endocrinol Metab. 1997;82:136–42.PubMedGoogle Scholar
  21. 21.
    Nakamura S, Tan L, Nagata Y, Takemura T, Asahina A, Yokota D, et al. JmjC-domain containing histone demethylase 1B-mediated p15(Ink4b) suppression promotes the proliferation of leukemic progenitor cells through modulation of cell cycle progression in acute myeloid leukemia. Mol Carcinog. 2013;52:57–69.CrossRefPubMedGoogle Scholar
  22. 22.
    Allen M, Louise JJ. Jekyll and Hyde: the role of the microenvironment on the progression of cancer. J Pathol. 2011;223:162–76.PubMedGoogle Scholar
  23. 23.
    Swartz MA, Iida N, Roberts EW, Sangaletti S, Wong MH, Yull FE, et al. Tumor microenvironment complexity: emerging roles in cancer therapy. Cancer Res. 2012;72:2473–80.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Fu S, Dong L, Sun W, Xu Y, Gao L, Miao Y. Stromal-epithelial crosstalk provides a suitable microenvironment for the progression of ovarian cancer cells in vitro. Cancer Investig. 2013;31:616–24.CrossRefGoogle Scholar
  25. 25.
    Di Cristofano A, Ellenson LH. Endometrial carcinoma. Annu Rev Pathol. 2007;2:57–85.CrossRefPubMedGoogle Scholar
  26. 26.
    Hecht JL, Mutter GL. Molecular and pathologic aspects of endometrial carcinogenesis. J Clin Oncol. 2006;24:4783–91.CrossRefPubMedGoogle Scholar
  27. 27.
    Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275:1943–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Salmena L, Carracedo A, Pandolfi PP. Tenets of PTEN tumor suppression. Cell. 2008;133:403–14.CrossRefPubMedGoogle Scholar
  29. 29.
    van Houdt WJ, de Bruijn MT, Emmink BL, Raats D, Hoogwater FJ, Borel RI, et al. Oncogenic K-ras activates p38 to maintain colorectal cancer cell proliferation during MEK inhibition. Cell Oncol. 2010;32:245–57.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153–66.CrossRefPubMedGoogle Scholar
  31. 31.
    Kato J, Matsushime H, Hiebert SW, Ewen ME, Sherr CJ. Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev. 1993;7:331–42.CrossRefPubMedGoogle Scholar
  32. 32.
    Lundberg AS, Weinberg RA. Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes. Mol Cell Biol. 1998;18:753–61.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL. Cyclin D as a therapeutic target in cancer. Nat Rev Cancer. 2011;11:558–72.CrossRefPubMedGoogle Scholar
  34. 34.
    Steffan JJ, Coleman DT, Cardelli JA. The HGF-met signaling axis: emerging themes and targets of inhibition. Curr Protein Pept Sci. 2011;12:12–22.CrossRefPubMedGoogle Scholar
  35. 35.
    Atif F, Yousuf S, Stein DG. Anti-tumor effects of progesterone in human glioblastoma multiforme: Role of PI3K/Akt/mTOR signaling. J Steroid Biochem Mol Biol. 2014.Google Scholar
  36. 36.
    Chatterjee M, Andrulis M, Stuhmer T, Muller E, Hofmann C, Steinbrunn T, et al. The PI3K/Akt signaling pathway regulates the expression of Hsp70, which critically contributes to Hsp90-chaperone function and tumor cell survival in multiple myeloma. Haematologica. 2013;98:1132–41.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Samartzis EP, Noske A, Dedes KJ, Fink D, Imesch P. ARID1A mutations and PI3K/AKT pathway alterations in endometriosis and endometriosis-associated ovarian carcinomas. Int J Mol Sci. 2013;14:18824–49.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Salvesen HB, Carter SL, Mannelqvist M, Dutt A, Getz G, Stefansson IM, et al. Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation. Proc Natl Acad Sci U S A. 2009;106:4834–9.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Li H, Zeng J, Shen K. PI3K/AKT/mTOR signaling pathway as a therapeutic target for ovarian cancer. Arch Gynecol Obstet. 2014;290:1067–78.CrossRefPubMedGoogle Scholar
  40. 40.
    Pavlidou A, Vlahos NF. Molecular alterations of PI3K/Akt/mTOR pathway: a therapeutic target in endometrial cancer. ScientificWorldJournal. 2014;2014:709736.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Slomovitz BM, Coleman RL. The PI3K/AKT/mTOR pathway as a therapeutic target in endometrial cancer. Clin Cancer Res. 2012;18:5856–64.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  2. 2.South Branch of the Six People’s Hospital Affiliated to Shanghai Jiao Tong UniversityShanghaiChina

Personalised recommendations