Skip to main content

Advertisement

SpringerLink
Log in

Mutual concessions and compromises between stromal cells and cancer cells: driving tumor development and drug resistance

  • Review
  • Published:
Cellular Oncology Aims and scope Submit manuscript

Abstract

Background

Various cancers have been found to be associated with heterogeneous and adaptive tumor microenvironments (TMEs) and to be driven by the local TMEs in which they thrive. Cancer heterogeneity plays an important role in tumor cell survival, progression and drug resistance. The diverse cellular components of the TME may include cancer-associated fibroblasts, adipocytes, pericytes, mesenchymal stem cells, endothelial cells, lymphocytes and other immune cells. These components may support tumor development through the secretion of growth factors, evasion from immune checkpoints, metabolic adaptations, modulations of the extracellular matrix, activation of oncogenes and the acquisition of drug resistance. Here, we will address recent advances in our understanding of the molecular mechanisms underlying stromal-tumor cell interactions, with special emphasis on basic and pre-clinical information that may facilitate the design of novel personalized cancer therapies.

Conclusions

This review presents a holistic view on the translational potential of the interplay between stromal cells and cancer cells. This interplay is currently being employed for the development of promising preclinical and clinical biomarkers, and the design of small molecule inhibitors, antibodies and small RNAs for (combinatorial) cancer treatment options. In addition, nano-carriers, tissue scaffolds and 3-D based matrices are being developed to precisely and safely deliver these compounds.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. M. Plummer, C. de Martel, J. Vignat, J. Ferlay, F. Bray, S. Franceschi, Global burden of cancers attributable to infections in 2012: A synthetic analysis. Lancet Glob. Health 4, e609–e616 (2016)

    Article  Google Scholar 

  2. J. Bishop, The molecular genetics of cancer. Science 235, 305–311 (1987)

    Article  PubMed  CAS  Google Scholar 

  3. M.M. Gottesman, Mechanisms of cancer drug resistance. Annu. Rev. Med. 53, 615–627 (2002)

    Article  PubMed  CAS  Google Scholar 

  4. A.A. Alizadeh, V. Aranda, A. Bardelli, C. Blanpain, C. Bock, C. Borowski, C. Caldas, A. Califano, M. Doherty, M. Elsner, M. Esteller, R. Fitzgerald, J.O. Korbel, P. Lichter, C.E. Mason, N. Navin, D. Peer, K. Polyak, C.W.M. Roberts, L. Siu, A. Snyder, H. Stower, C. Swanton, R.G.W. Verhaak, J.C. Zenklusen, J. Zuber, J. Zucman-Rossi, Toward understanding and exploiting tumor heterogeneity. Nat. Med. 21, 846–853 (2015)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. J.W. Clark, B.A. Chabner, Limits to precision cancer medicine. N. Engl. J. Med. 376, 95–97 (2017)

    Article  Google Scholar 

  6. L.A. Liotta, E.C. Kohn, The microenvironment of the tumour host interface. Nature 411, 375–379 (2001)

    Article  PubMed  CAS  Google Scholar 

  7. B.S. Wiseman, Stromal effects on mammary gland development and breast cancer. Science 296, 1046–1049 (2002)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. J.W. Pollard, Tumour-educated macrophages promote tumour progression and metastasis. Nat. Rev. Cancer 4, 71–78 (2004)

    Article  PubMed  CAS  Google Scholar 

  9. V. Kumar, L. Donthireddy, D. Marvel, T. Condamine, F. Wang, S. Lavilla-Alonso, A. Hashimoto, P. Vonteddu, R. Behera, M.A. Goins, C. Mulligan, B. Nam, N. Hockstein, F. Denstman, S. Shakamuri, D.W. Speicher, A.T. Weeraratna, T. Chao, R.H. Vonderheide, L.R. Languino, P. Ordentlich, Q. Liu, X. Xu, A. Lo, E. Puré, C. Zhang, A. Loboda, M.A. Sepulveda, L.A. Snyder, D.I. Gabrilovich, Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell 32 e655, 654–668 (2017)

  10. Y. Qiao, C. Zhang, A. Li, D. Wang, Z. Luo, Y. Ping, B. Zhou, S. Liu, H. Li, D. Yue, Z. Zhang, X. Chen, Z. Shen, J. Lian, Y. Li, S. Wang, F. Li, L. Huang, L. Wang, B. Zhang, J. Yu, Z. Qin, Y. Zhang, IL6 derived from cancer-associated fibroblasts promotes chemoresistance via CXCR7 in esophageal squamous cell carcinoma. Oncogene 37, 873–883 (2017). https://doi.org/10.1038/onc.2017.387

    Article  PubMed  CAS  Google Scholar 

  11. H.G. Augustin, G.Y. Koh, Organotypic vasculature: From descriptive heterogeneity to functional pathophysiology. Science 357, eaal2379 (2017)

    Article  PubMed  CAS  Google Scholar 

  12. M. Spaw, S. Anant, S.M. Thomas, Stromal contributions to the carcinogenic process. Mol. Carcinog. 56, 1199–1213 (2017)

    Article  PubMed  CAS  Google Scholar 

  13. T. Shibue, R.A. Weinberg, EMT, CSCs, and drug resistance: The mechanistic link and clinical implications. Nat. Rev. Clin. Oncol. 14, 611–629 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  14. M. Cheng, S. Ho, J.H. Yoo, D.H. Tran, K. Bakirtzi, B. Su, D.H. Tran, Y. Kubota, R. Ichikawa, H.W. Koon, Cathelicidin suppresses colon cancer development by inhibition of cancer associated fibroblasts. Clin. Exp. Gastroenterol. 8, 13–29 (2015)

    PubMed  CAS  Google Scholar 

  15. V. Gkretsi, A. Stylianou, P. Papageorgis, C. Polydorou, T. Stylianopoulos, Remodeling components of the tumor microenvironment to enhance cancer therapy. Front. Oncol. 5, 214 (2015)

  16. D. Jahagirdar, S. Purohit, A. Jain, N.K. Sharma, Export of microRNAs: A bridge between breast carcinoma and their neighboring cells. Front. Oncol. 6, 147 (2016)

  17. M. Najar, H. Fayyad-Kazan, W.H. Faour, B. Badran, F. Journe, L. Lagneaux, Breast cancer cells and bone marrow mesenchymal stromal cells: A regulated modulation of the breast tumor in the context of immune response. Inflamm. Res. 66, 129–139 (2017)

    Article  PubMed  CAS  Google Scholar 

  18. P. Nilendu, A. Kumar, A. Kumar, J.K. Pal, N.K. Sharma, Breast cancer stem cells as last soldiers eluding therapeutic burn: A hard nut to crack. Int. J. Cancer 142, 7–17 (2017)

    Article  PubMed  CAS  Google Scholar 

  19. R. Kalluri, The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–598 (2016)

    Article  PubMed  CAS  Google Scholar 

  20. P.J. Morin, in Cancer Drug Resistance, ed. by B.A. Teicher (Humana Press, Totowa, NJ, 2006), pp. 201–210

  21. A. Morandi, E. Giannoni, P. Chiarugi, Nutrient exploitation within the tumor–stroma metabolic crosstalk. Trends Cancer 2, 736–746 (2016)

    Article  PubMed  Google Scholar 

  22. K. Cyll, E. Ersvær, L. Vlatkovic, M. Pradhan, W. Kildal, M.A. Kjær, A. Kleppe, T.S. Hveem, B. Carlsen, S. Gill, S. Löffeler, E.S. Haug, H. Wæhre, P. Sooriakumaran, H.E. Danielsen, Tumour heterogeneity poses a significant challenge to cancer biomarker research. Br. J. Cancer 117, 367–375 (2017)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. M. Majidinia, B. Yousefi, Breast tumor stroma: A driving force in the development of resistance to therapies. Chem. Biol. Drug Des. 89, 309–318 (2017)

    Article  PubMed  CAS  Google Scholar 

  24. N. McGranahan, C. Swanton, Clonal heterogeneity and tumor evolution: Past, present, and the future. Cell 168, 613–628 (2017)

    Article  PubMed  CAS  Google Scholar 

  25. N. Picco, E. Sahai, P.K. Maini, A.R.A. Anderson, Integrating models to quantify environment-mediated drug resistance. Cancer Res. 77, 5409–5418 (2017)

    Article  PubMed  CAS  Google Scholar 

  26. R.F. Schwabe, C. Jobin, The microbiome and cancer. Nat. Rev. Cancer 13, 800–812 (2013)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. A.L. Ribeiro, O.K. Okamoto, Combined effects of pericytes in the tumor microenvironment. Stem Cells Int. 868475, 2015 (2015)

  28. C.C. Maley, A. Aktipis, T.A. Graham, A. Sottoriva, A.M. Boddy, Classifying the evolutionary and ecological features of neoplasms. Nat. Rev. Cancer 17, 605–619 (2017)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. H. Omar Al-Hassi, O. Ng, M. Brookes, Tumour-associated and non-tumour-associated microbiota in colorectal cancer. Gut 67, 395 (2018)

    Article  PubMed  Google Scholar 

  30. E. Perez-Chanona, G. Trinchieri, The role of microbiota in cancer therapy. Curr. Opin. Immunol. 39, 75–81 (2016)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Z. Benyahia, N. Dussault, M. Cayol, R. Sigaud, C. Berenguer-Daize, C. Delfino, A. Tounsi, S. Garcia, P.M. Martin, K. Mabrouk, L. Ouafik, Stromal fibroblasts present in breast carcinomas promote tumor growth and angiogenesis through adrenomedullin secretion. Oncotarget 8, 15744–15762 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  32. L. Bolm, S. Cigolla, U.A. Wittel, U.T. Hopt, T. Keck, D. Rades, P. Bronsert, U.F. Wellner, The role of fibroblasts in pancreatic cancer: Extracellular matrix versus paracrine factors. Transl. Oncol. 10, 578–588 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  33. N. Cohen, O. Shani, Y. Raz, Y. Sharon, D. Hoffman, L. Abramovitz, N. Erez, Fibroblasts drive an immunosuppressive and growth-promoting microenvironment in breast cancer via secretion of Chitinase 3-like 1. Oncogene 36, 4457–4468 (2017)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. N.A. Bhowmick, E.G. Neilson, H.L. Moses, Stromal fibroblasts in cancer initiation and progression. Nature 432, 332–337 (2004)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. A. Aboussekhra, Role of cancer-associated fibroblasts in breast cancer development and prognosis. Int. J. Dev. Biol. 55, 841–849 (2011)

    Article  PubMed  Google Scholar 

  36. U.M. Polanska, A. Orimo, Carcinoma-associated fibroblasts: Non-neoplastic tumour-promoting mesenchymal cells. J. Cell. Physiol. 228, 1651–1657 (2013)

    Article  PubMed  CAS  Google Scholar 

  37. H. Luo, G. Tu, Z. Liu, M. Liu, Cancer-associated fibroblasts: A multifaceted driver of breast cancer progression. Cancer Lett. 361, 155–163 (2015)

    Article  PubMed  CAS  Google Scholar 

  38. A. Orimo, R.A. Weinberg, Stromal fibroblasts in cancer: A novel tumor-promoting cell type. Cell Cycle 5, 1597–1601 (2006)

    Article  PubMed  CAS  Google Scholar 

  39. G.S. Markopoulos, E. Roupakia, M. Tokamani, E. Chavdoula, M. Hatziapostolou, C. Polytarchou, K.B. Marcu, A.G. Papavassiliou, R. Sandaltzopoulos, E. Kolettas, A step-by-step microRNA guide to cancer development and metastasis. Cell. Oncol. 40, 303–339 (2017)

    Article  CAS  Google Scholar 

  40. P. Mishra, D. Banerjee, A. Ben-Baruch, Chemokines at the crossroads of tumor-fibroblast interactions that promote malignancy. J. Leukoc. Biol. 89, 31–39 (2011)

    Article  PubMed  CAS  Google Scholar 

  41. K.O. Osuala, M. Sameni, S. Shah, N. Aggarwal, M.L. Simonait, O.E. Franco, Y. Hong, S.W. Hayward, F. Behbod, R.R. Mattingly, B.F. Sloane, Il-6 signaling between ductal carcinoma in situ cells and carcinoma-associated fibroblasts mediates tumor cell growth and migration. BMC Cancer 15, 584 (2015)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Ö. Sağlam, Z.S. Ünal, C. Subaşı, E. Ulukaya, E. Karaöz, IL-6 originated from breast cancer tissue-derived mesenchymal stromal cells may contribute to carcinogenesis. Tumour Biol. 36, 5667–5677 (2015)

    Article  PubMed  CAS  Google Scholar 

  43. D. von Ahrens, T.D. Bhagat, D. Nagrath, A. Maitra, A. Verma, The role of stromal cancer-associated fibroblasts in pancreatic cancer. J. Hematol. Oncol. 10, 76 (2017)

  44. S.-F. Hendrayani, H.H. Al-Khalaf, A. Aboussekhra, The cytokine IL-6 reactivates breast stromal fibroblasts through transcription factor STAT3-dependent up-regulation of the RNA-binding protein AUF1. J. Biol. Chem. 289, 30962–30976 (2014)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. T. Ishimoto, K. Miyake, T. Nandi, M. Yashiro, N. Onishi, K.K. Huang, S.J. Lin, R. Kalpana, S.T. Tay, Y. Suzuki, B.C. Cho, D. Kuroda, K. Arima, D. Izumi, M. Iwatsuki, Y. Baba, E. Oki, M. Watanabe, H. Saya, K. Hirakawa, H. Baba, P. Tan, Activation of transforming growth factor beta 1 signaling in gastric cancer-associated fibroblasts increases their motility, via expression of rhomboid 5 homolog 2, and ability to induce invasiveness of gastric cancer cells. Gastroenterology 153, 191-204. e116 (2017), 204.e16

  46. E. Sjöberg, M. Augsten, J. Bergh, K. Jirström, A. Östman, Expression of the chemokine CXCL14 in the tumour stroma is an independent marker of survival in breast cancer. Br. J. Cancer 114, 1117–1124 (2016)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. M. Yao, E. Yu, V. Staggs, F. Fan, N. Cheng, Elevated expression of chemokine C-C ligand 2 in stroma is associated with recurrent basal-like breast cancers. Mod. Pathol. 29, 810–823 (2016)

    Article  PubMed  CAS  Google Scholar 

  48. L. Zhao, G. Ji, X. Le, Z. Luo, C. Wang, M. Feng, L. Xu, Y. Zhang, W.B. Lau, B. Lau, Y. Yang, L. Lei, H. Yang, Y. Xuan, Y. Chen, X. Deng, T. Yi, S. Yao, X. Zhao, Y. Wei, S. Zhou, An integrated analysis identifies STAT4 as a key regulator of ovarian cancer metastasis. Oncogene 36, 3384–3396 (2017)

    Article  PubMed  CAS  Google Scholar 

  49. N. Kramer, J. Schmöllerl, C. Unger, H. Nivarthi, A. Rudisch, D. Unterleuthner, M. Scherzer, A. Riedl, M. Artaker, I. Crncec, D. Lenhardt, T. Schwarz, B. Prieler, X. Han, M. Hengstschläger, J. Schüler, R. Eferl, R. Moriggl, W. Sommergruber, H. Dolznig, Autocrine WNT2 signaling in fibroblasts promotes colorectal cancer progression. Oncogene 36, 5460–5472 (2017)

    Article  PubMed  CAS  Google Scholar 

  50. A. Avgustinova, M. Iravani, D. Robertson, A. Fearns, Q. Gao, P. Klingbeil, A.M. Hanby, V. Speirs, E. Sahai, F. Calvo, C.M. Isacke, Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness. Nat. Commun. 7, 10305 (2016)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. J.S.K. Chan, M.K. Sng, Z.Q. Teo, H.C. Chong, J.S. Twang, N.S. Tan, Targeting nuclear receptors in cancer-associated fibroblasts as concurrent therapy to inhibit development of chemoresistant tumors. Oncogene 37, 160–173 (2017)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. M.P. Pinto, W.W. Dye, B.M. Jacobsen, K.B. Horwitz, Malignant stroma increases luminal breast cancer cell proliferation and angiogenesis through platelet-derived growth factor signaling. BMC Cancer 14, 735 (2014)

  53. Y. Kitadai, T. Sasaki, T. Kuwai, T. Nakamura, C.D. Bucana, S.R. Hamilton, I.J. Fidler, 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 (2006)

    Article  PubMed  CAS  Google Scholar 

  54. S. Neri, T. Miyashita, H. Hashimoto, Y. Suda, M. Ishibashi, H. Kii, H. Watanabe, T. Kuwata, M. Tsuboi, K. Goto, T. Menju, M. Sonobe, H. Date, A. Ochiai, G. Ishii, Fibroblast-led cancer cell invasion is activated by epithelial–mesenchymal transition through platelet-derived growth factor BB secretion of lung adenocarcinoma. Cancer Lett. 395, 20–30 (2017)

    Article  PubMed  CAS  Google Scholar 

  55. P.S.H. Soon, E. Kim, C.K. Pon, A.J. Gill, K. Moore, A.J. Spillane, D.E. Benn, R.C. Baxter, Breast cancer-associated fibroblasts induce epithelial-to-mesenchymal transition in breast cancer cells. Endocr. Relat. Cancer 20, 1–12 (2013)

    Article  PubMed  CAS  Google Scholar 

  56. A. Orimo, P.B. Gupta, D.C. Sgroi, F. Arenzana-Seisdedos, T. Delaunay, R. Naeem, V.J. Carey, A.L. Richardson, R.A. Weinberg, Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121, 335–348 (2005)

    Article  PubMed  CAS  Google Scholar 

  57. N.L.E. Harris, C. Vennin, J.R.W. Conway, K.L. Vine, M. Pinese, M.J. Cowley, R.F. Shearer, M.C. Lucas, D. Herrmann, A.H. Allam, M. Pajic, J.P. Morton, A.V. Biankin, M. Ranson, P. Timpson, D.N. Saunders, SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer. Oncogene 36, 4288–4298 (2017)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. N. Perurena, C. Zandueta, S. Martínez-Canarias, H. Moreno, S. Vicent, A.S. Almeida, E. Guruceaga, R.R. Gomis, M. Santisteban, M. Egeblad, EPCR promotes breast cancer progression by altering SPOCK1/testican 1-mediated 3D growth. J. Hematol. Oncol. 10, 23 (2017)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. S. Busch, A. Acar, Y. Magnusson, P. Gregersson, L. Ryden, G. Landberg, TGF-beta receptor type-2 expression in cancer-associated fibroblasts regulates breast cancer cell growth and survival and is a prognostic marker in pre-menopausal breast cancer. Oncogene 34, 27–38 (2015)

    Article  PubMed  CAS  Google Scholar 

  60. A.M. Hammer, G.M. Sizemore, V.C. Shukla, A. Avendano, S.T. Sizemore, J.J. Chang, R.D. Kladney, M.C. Cuitiño, K.A. Thies, Q. Verfurth, A. Chakravarti, L.D. Yee, G. Leone, J.W. Song, S.N. Ghadiali, M.C. Ostrowski, Stromal PDGFR-α activation enhances matrix stiffness, impedes mammary ductal development, and accelerates tumor growth. Neoplasia 19, 496–508 (2017)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Y. Kinugasa, T. Matsui, N. Takakura, CD44 expressed on cancer-associated fibroblasts is a functional molecule supporting the stemness and drug resistance of malignant cancer cells in the tumor microenvironment. Stem Cells 32, 145–156 (2014)

    Article  PubMed  CAS  Google Scholar 

  62. B.Y. Owusu, S. Thomas, P. Venukadasula, Z. Han, J.W. Janetka, R.A. Galemmo Jr., L. Klampfer, Targeting the tumor-promoting microenvironment in MET-amplified NSCLC cells with a novel inhibitor of pro-HGF activation. Oncotarget 8, 63014–63025 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  63. J. Paulsson, L. Rydén, C. Strell, O. Frings, N.P. Tobin, T. Fornander, J. Bergh, G. Landberg, O. Stål, A. Östman, High expression of stromal PDGFRβ is associated with reduced benefit of tamoxifen in breast cancer. J. Pathol. Clin. Res. 3, 38–43 (2016)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. C.A.S. Corsa, A. Brenot, W.R. Grither, S. Van Hove, A.J. Loza, K. Zhang, S.M. Ponik, Y. Liu, D.G. DeNardo, K.W. Eliceiri, P.J. Keely, G.D. Longmore, The action of discoidin domain receptor 2 in basal tumor cells and stromal cancer-associated fibroblasts is critical for breast cancer metastasis. Cell Rep. 15, 2510–2523 (2016)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. X. Li, W. Zhu, Z. Chen, L. Luo, J. Huang, F. Zhang, M. Li, Y. Guo, L. Guo, Fibroblast growth factor-inducible 14 regulates cell growth and multidrug resistance of small-cell lung cancer through the nuclear factor-κB pathway. Anti-Cancer Drugs 25, 1152–1164 (2014)

    Article  PubMed  CAS  Google Scholar 

  66. E.M. De Francesco, A.H. Sims, M. Maggiolini, F. Sotgia, M.P. Lisanti, R.B. Clarke, GPER mediates the angiocrine actions induced by IGF1 through the HIF-1alpha/VEGF pathway in the breast tumor microenvironment. Breast Cancer Res. 19, 129 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  67. S.Y. Yeo, S.Y. Ha, K.W. Lee, Y. Cui, Z.T. Yang, Y.H. Xuan, S.H. Kim, Twist1 is highly expressed in cancer-associated fibroblasts of esophageal squamous cell carcinoma with a prognostic significance. Oncotarget 8, 65265–65280 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  68. D.E. Kim, M.-G. Procopio, S. Ghosh, S.-H. Jo, S. Goruppi, F. Magliozzi, P. Bordignon, V. Neel, P. Angelino, G.P. Dotto, Convergent roles of ATF3 and CSL in chromatin control of cancer-associated fibroblast activation. J. Exp. Med. 214, 2349–2368 (2017)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. W.N. Brennen, D.M. Rosen, H. Wang, J.T. Isaacs, S.R. Denmeade, Targeting carcinoma-associated fibroblasts within the tumor stroma with a fibroblast activation protein-activated prodrug. J. Natl. Cancer Inst. 104, 1320–1334 (2012)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. U.E. Martinez-Outschoorn, M.P. Lisanti, F. Sotgia, Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth. Semin. Cancer Biol. 25, 47–60 (2014)

    Article  PubMed  CAS  Google Scholar 

  71. B.B. Patel, E. Ackerstaff, I.S. Serganova, J.E. Kerrigan, R.G. Blasberg, J.A. Koutcher, D. Banerjee, Tumor stroma interaction is mediated by monocarboxylate metabolism. Exp. Cell Res. 352, 20–33 (2017)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. B. Chiavarina, D. Whitaker-Menezes, U.E. Martinez-Outschoorn, A.K. Witkiewicz, R. Birbe, A. Howell, R.G. Pestell, J. Smith, R. Daniel, F. Sotgia, M.P. Lisanti, Pyruvate kinase expression (PKM1 and PKM2) in cancer-associated fibroblasts drives stromal nutrient production and tumor growth. Cancer Biol. Ther. 12, 1101–1113 (2011)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. F. Lopes-Coelho, S. Andre, A. Felix, J. Serpa, Breast cancer metabolic cross-talk: Fibroblasts are hubs and breast cancer cells are gatherers of lipids. Mol. Cell. Endocrinol. 462, 93–106 (2018)

    Article  PubMed  CAS  Google Scholar 

  74. X. Tang, Y. Hou, G. Yang, X. Wang, S. Tang, Y.E. Du, L. Yang, T. Yu, H. Zhang, M. Zhou, S. Wen, L. Xu, M. Liu, Stromal miR-200s contribute to breast cancer cell invasion through CAF activation and ECM remodeling. Cell Death Differ. 23, 132–145 (2016)

  75. Y. Liu, J. Zhang, X. Sun, Q. Su, C. You, Down-regulation of miR-29b in carcinoma associated fibroblasts promotes cell growth and metastasis of breast cancer. Oncotarget 8, 39559–39570 (2017)

    PubMed  PubMed Central  Google Scholar 

  76. C.J. Clarke, T.J. Berg, J. Birch, D. Ennis, L. Mitchell, C. Cloix, A. Campbell, D. Sumpton, C. Nixon, K. Campbell, V.L. Bridgeman, P.B. Vermeulen, S. Foo, E. Kostaras, J.L. Jones, L. Haywood, E. Pulleine, H. Yin, D. Strathdee, O. Sansom, K. Blyth, I. McNeish, S. Zanivan, A.R. Reynolds, J.C. Norman, The initiator methionine tRNA drives secretion of type II collagen from stromal fibroblasts to promote tumor growth and angiogenesis. Curr. Biol. 26, 755–765 (2016)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. K.H. Vousden, Lane D.P. p53 in health and disease. Nat. Rev. 8, 275–283 (2007)

    Article  CAS  Google Scholar 

  78. A.J. Levine, p53, the cellular gatekeeper for growth and division. Cell 88, 323–331 (1997)

    Article  PubMed  CAS  Google Scholar 

  79. M.S. Song, L. Salmena, P.P. Pandolfi, The functions and regulation of the PTEN tumour suppressor. Nat. Rev. Mol. Cell Biol. 13, 283–296 (2012)

    Article  PubMed  CAS  Google Scholar 

  80. M.G. Procopio, C. Laszlo, D. Al Labban, D.E. Kim, P. Bordignon, S.H. Jo, S. Goruppi, E. Menietti, Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation. Nat. Cell Biol. 17, 1193–1204 (2015)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. P. Dauer, X. Zhao, V.K. Gupta, N. Sharma, K. Kesh, P. Gnamlin, Inactivation of Cancer-associated-fibroblasts disrupts oncogenic signaling in pancreatic Cancer cells and promotes its regression. Cancer Res. 78, 1321–1333 (2018)

    Article  PubMed  CAS  Google Scholar 

  82. Y. Hayashi, M. Tsujii, T. Kodama, T. Akasaka, J. Kondo, H. Hikita, T. Inoue, p53 functional deficiency in human colon cancer cells promotes fibroblast-mediated angiogenesis and tumor growth. Carcinogenesis 37, 972–984 (2016)

    Article  PubMed  CAS  Google Scholar 

  83. J.O. Schmid, M. Dong, S. Haubeiss, G. Friedel, S. Bode, A. Grabner, G. Ott, T.E. Mürdter, Cancer cells cue the p53 response of cancer-associated fibroblasts to cisplatin. Cancer Res. 72, 5824–5832 (2012)

    Article  PubMed  CAS  Google Scholar 

  84. C.P. Liao, H. Adisetiyo, M. Liang, P. Roy-Burman, Cancer-associated fibroblasts enhance the gland-forming capability of prostate cancer stem cells. Cancer Res. 70, 7294–7303 (2010)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. A.J. Trimboli, C.Z. Cantemir-Stone, F. Li, J.A. Wallace, A. Merchant, N. Creasap, Pten in stromal fibroblasts suppresses mammary epithelial tumors. Nature 461, 1084–1091 (2009)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. G.M. Sizemore, H.A.M. Balakrishnan, K.A. Thies, A.J. Trimboli, J.A. Wallace, Stromal PTEN inhibits the expansion of mammary epithelial stem cells through Jagged-1. Oncogene 36, 2297–2308 (2017)

    Article  PubMed  CAS  Google Scholar 

  87. J. Park, P.E. Scherer, Adipocyte-derived endotrophin promotes malignant tumor progression. J. Clin. Invest. 122, 4243–4256 (2012)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. L. Bochet, C. Lehuede, S. Dauvillier, Y.Y. Wang, B. Dirat, V. Laurent, C. Dray, R. Guiet, I. Maridonneau-Parini, S. Le Gonidec, B. Couderc, G. Escourrou, P. Valet, C. Muller, Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer. Cancer Res. 73, 5657–5668 (2013)

    Article  PubMed  CAS  Google Scholar 

  89. K.M. Nieman, I.L. Romero, B. Van Houten, E. Lengyel, Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochim. Biophys. Acta 1831, 1533–1541 (2013)

    CAS  Google Scholar 

  90. J. Zhang, L. Zhang, C. Li, C. Yang, L. Li, S. Song, H. Wu, F. Liu, L. Wang, J. Gu, LOX-1 is a poor prognostic indicator and induces epithelial-mesenchymal transition and metastasis in pancreatic cancer patients. Cell. Oncol. 41, 73–84 (2018)

    Article  CAS  Google Scholar 

  91. Y. Lee, W.H. Jung, J.S. Koo, Adipocytes can induce epithelial-mesenchymal transition in breast cancer cells. Breast Cancer Res. Treat. 153, 323–335 (2015)

    Article  PubMed  CAS  Google Scholar 

  92. C.-K. Huang, P.-H. Chang, W.-H. Kuo, C.-L. Chen, Y.-M. Jeng, K.-J. Chang, J.-Y. Shew, C.-M. Hu, W.-H. Lee, Adipocytes promote malignant growth of breast tumours with monocarboxylate transporter 2 expression via β-hydroxybutyrate. Nat. Commun. 8, 14706 (2017)

  93. Z. Jia, Y. Liu, S. Cui, Adiponectin induces breast cancer cell migration and growth factor expression. Cell Biochem. Biophys. 70, 1239–1245 (2014)

    Article  PubMed  CAS  Google Scholar 

  94. A. Yao-Borengasser, B. Monzavi-Karbassi, R.A. Hedges, L.J. Rogers, S.A. Kadlubar, T. Kieber-Emmons, Adipocyte hypoxia promotes epithelial-mesenchymal transition-related gene expression and estrogen receptor-negative phenotype in breast cancer cells. Oncol. Rep. 33, 2689–2694 (2015)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. C. Wang, C. Gao, K. Meng, H. Qiao, Y. Wang, Human adipocytes stimulate invasion of breast cancer MCF-7 cells by secreting IGFBP-2. PLoS One 10, e0119348 (2015)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. X. Catteau, P. Simon, J.-C. NoëL, Stromal expression of matrix metalloproteinase 2 in cancer-associated fibroblasts is strongly related to human epidermal growth factor receptor 2 status in invasive breast carcinoma. Mol. Clin. Oncol. 4, 375–378 (2016)

    Article  PubMed  CAS  Google Scholar 

  97. V. D’Esposito, F. Passaretti, A. Hammarstedt, D. Liguoro, D. Terracciano, G. Molea, L. Canta, C. Miele, U. Smith, F. Beguinot, P. Formisano, Adipocyte-released insulin-like growth factor-1 is regulated by glucose and fatty acids and controls breast cancer cell growth in vitro. Diabetologia 55, 2811–2822 (2012)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. L. Bochet, A. Meulle, S. Imbert, B. Salles, P. Valet, C. Muller, Cancer-associated adipocytes promotes breast tumor radioresistance. Biochem. Biophys. Res. Commun. 411, 102–106 (2011)

    Article  PubMed  CAS  Google Scholar 

  99. K. Fujisaki, H. Fujimoto, T. Sangai, T. Nagashima, M. Sakakibara, N. Shiina, M. Kuroda, Y. Aoyagi, M. Miyazaki, Cancer-mediated adipose reversion promotes cancer cell migration via IL-6 and MCP-1. Breast Cancer Res. Treat. 150, 255–263 (2015)

    Article  PubMed  CAS  Google Scholar 

  100. V. D'Esposito, D. Liguoro, M.R. Ambrosio, F. Collina, M. Cantile, R. Spinelli, G.A. Raciti, C. Miele, R. Valentino, P. Campiglia, M. De Laurentiis, M. Di Bonito, G. Botti, R. Franco, F. Beguinot, P. Formisano, Adipose microenvironment promotes triple negative breast cancer cell invasiveness and dissemination by producing CCL5. Oncotarget 7, 24495–24509 (2016)

  101. M.N. Duong, A. Cleret, E.L. Matera, K. Chettab, D. Mathe, S. Valsesia-Wittmann, B. Clemenceau, C. Dumontet, Adipose cells promote resistance of breast cancer cells to trastuzumab-mediated antibody-dependent cellular cytotoxicity. Breast Cancer Res. 17, 57 (2015)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. D. Katoh, M. Nishizuka, S. Osada, M. Imagawa, Fad104, a positive regulator of adipocyte differentiation, suppresses invasion and metastasis of melanoma cells by inhibition of STAT3 activity. PLoS One 10, e0117197 (2015)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. A.L. Ribeiro, C. Kaid, P.B.G. Silva, B.A. Cortez, O.K. Okamoto, Inhibition of lysyl oxidases impairs migration and angiogenic properties of tumor-associated pericytes. Stem Cells Int. 4972078, 2017 (2017)

  104. K. Hosaka, Y. Yang, T. Seki, C. Fischer, O. Dubey, E. Fredlund, J. Hartman, P. Religa, H. Morikawa, Y. Ishii, M. Sasahara, O. Larsson, G. Cossu, R. Cao, S. Lim, Y. Cao, Pericyte–fibroblast transition promotes tumor growth and metastasis. Proc. Natl. Acad. Sci. U. S. A. 113, E5618–E5627 (2016)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. J. Hong, N.P. Tobin, H. Rundqvist, T. Li, M. Lavergne, Y. García-Ibáñez, H. Qin, J. Paulsson, M. Zeitelhofer, M.Z. Adzemovic, I. Nilsson, P. Roswall, J. Hartman, R.S. Johnson, A. Östman, J. Bergh, M. Poljakovic, G. Genové, Role of tumor pericytes in the recruitment of myeloid-derived suppressor cells. J. Natl. Cancer Inst. 107, djv209 (2015)

    Article  PubMed  CAS  Google Scholar 

  106. J.H. Trevino-Villarreal, R. Sepulveda, D.A. Cotanche, R.A. Rogers, Effect of pericytes on epithelial-to-mesenchymal transition in melanoma. J. Clin. Oncol. 30, 84–84 (2012)

    Article  Google Scholar 

  107. M. Teichert, L. Milde, A. Holm, L. Stanicek, N. Gengenbacher, S. Savant, T. Ruckdeschel, Z. Hasanov, K. Srivastava, J. Hu, S. Hertel, A. Bartol, K. Schlereth, H.G. Augustin, Pericyte-expressed Tie2 controls angiogenesis and vessel maturation. Nat. Commun. 8, 16106 (2017)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. L.E. Reynolds, G. D'Amico, T. Lechertier, A. Papachristodoulou, J.M. Muñoz-Félix, A. De Arcangelis, M. Baker, B. Serrels, K.M. Hodivala-Dilke, Dual role of pericyte α6β1-integrin in tumour blood vessels. J. Cell Sci. 130, 1583–1595 (2017)

  109. D. Sinha, L. Chong, J. George, H. Schlüter, S. Mönchgesang, S. Mills, J. Li, C. Parish, D. Bowtell, P. Kaur, Pericytes promote malignant ovarian cancer progression in mice and predict poor prognosis in serous ovarian cancer patients. Clin. Cancer Res. 22, 1813–1824 (2015)

    Article  PubMed  CAS  Google Scholar 

  110. A. Chavez-Gonzalez, B. Bakhshinejad, K. Pakravan, M.L. Guzman, S. Babashah, Novel strategies for targeting leukemia stem cells: Sounding the death knell for blood cancer. Cell. Oncol. 40, 1–20 (2017)

    Article  CAS  Google Scholar 

  111. B. Leyh, A. Dittmer, T. Lange, J.W. Martens, J. Dittmer, Stromal cells promote anti-estrogen resistance of breast cancer cells through an insulin-like growth factor binding protein 5 (IGFBP5)/B-cell leukemia/lymphoma 3 (Bcl-3) axis. Oncotarget 6, 39307–39328 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  112. R.D. Guardia, B. Lopez-Millan, J.R. Lavoie, C. Bueno, J. Castaño, M. Gómez-Casares, S. Vives, L. Palomo, M. Juan, J. Delgado, M.L. Blanco, J. Nomdedeu, A. Chaparro, J.L. Fuster, E. Anguita, M. Rosu-Myles, P. Menéndez, Detailed characterization of mesenchymal stem/stromal cells from a large cohort of AML patients demonstrates a definitive link to treatment outcomes. Stem Cell Reports 8, 1573–1586 (2017)

    Article  CAS  Google Scholar 

  113. K.M. McAndrews, D.J. McGrail, N. Ravikumar, M.R. Dawson, Mesenchymal stem cells induce directional migration of invasive breast cancer cells through TGF-β. Sci. Rep. 5, 16941 (2015)

  114. H.H. Wang, Y.L. Cui, N.G. Zaorsky, J. Lan, L. Deng, X.L. Zeng, Z.Q. Wu, Z. Tao, W.H. Guo, Q.X. Wang, L.J. Zhao, Z.Y. Yuan, Y. Lu, P. Wang, M.B. Meng, Mesenchymal stem cells generate pericytes to promote tumor recurrence via vasculogenesis after stereotactic body radiation therapy. Cancer Lett. 375, 349–359 (2016)

  115. T.L. Watts, R. Cui, P. Szaniszlo, V.A. Resto, D.W. Powell, I.V. Pinchuk, PDGF-AA mediates mesenchymal stromal cell chemotaxis to the head and neck squamous cell carcinoma tumor microenvironment. J. Transl. Med. 14, 337 (2016)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. F. Ma, D. Chen, F. Chen, Y. Chi, Z. Han, X. Feng, X. Li, Z. Han, Human umbilical cord mesenchymal stem cells promote breast cancer metastasis by interleukin-8- and interleukin-6-dependent induction of CD44+/CD24- cells. Cell Transplant. 24, 2585–2599 (2015)

    Article  PubMed  Google Scholar 

  117. P.F. Yu, Y. Huang, C.L. Xu, L.Y. Lin, Y.Y. Han, W.H. Sun, G.H. Hu, A.B. Rabson, Y. Wang, Y.F. Shi, Downregulation of CXCL12 in mesenchymal stromal cells by TGFβ promotes breast cancer metastasis. Oncogene 36, 840–849 (2017)

    Article  PubMed  CAS  Google Scholar 

  118. A.C. Dudley, Tumor endothelial cells. Cold Spring Harb Perspect Med 2, a006536 (2012)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. A. Scholz, P.N. Harter, S. Cremer, B.H. Yalcin, S. Gurnik, M. Yamaji, M. Di Tacchio, K. Sommer, P. Baumgarten, O. Bahr, J.P. Steinbach, J. Trojan, M. Glas, U. Herrlinger, D. Krex, M. Meinhardt, A. Weyerbrock, M. Timmer, R. Goldbrunner, M. Deckert, C. Braun, J. Schittenhelm, J.T. Frueh, E. Ullrich, M. Mittelbronn, K.H. Plate, Y. Reiss, Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma. EMBO Mol. Med. 8, 39–57 (2016)

    Article  PubMed  CAS  Google Scholar 

  120. M.-Y. Hsu, M.H. Yang, C.I. Schnegg, S. Hwang, B. Ryu, R.M. Alani, Notch3 signaling-mediated melanoma–endothelial crosstalk regulates melanoma stem-like cell homeostasis and niche morphogenesis. Lab. Invest. 97, 725–736 (2017)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. E. Wieland, J. Rodriguez-Vita, S.S. Liebler, C. Mogler, I. Moll, S.E. Herberich, E. Espinet, E. Herpel, A. Menuchin, J. Chang-Claude, M. Hoffmeister, C. Gebhardt, H. Brenner, A. Trumpp, C.W. Siebel, M. Hecker, J. Utikal, D. Sprinzak, A. Fischer, Endothelial Notch1 activity facilitates metastasis. Cancer Cell 31, 355–367 (2017)

    Article  PubMed  CAS  Google Scholar 

  122. B. Balinisteanu, A.M. Cimpean, E. Melnic, M. Coculescu, R.A. Ceausu, M. Raica, Crosstalk between tumor blood vessels heterogeneity and hormonal profile of pituitary adenomas: Evidence and controversies. Anticancer Res. 34, 5413–5420 (2014)

    PubMed  Google Scholar 

  123. P. Ghiabi, J. Jiang, J. Pasquier, M. Maleki, N. Abu-Kaoud, N. Halabi, B.S. Guerrouahen, S. Rafii, A. Rafii, Breast cancer cells promote a notch-dependent mesenchymal phenotype in endothelial cells participating to a pro-tumoral niche. J. Transl. Med. 13, 27 (2015)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. R. Wilson, C. Espinosa-Diez, N. Kanner, N. Chatterjee, R. Ruhl, C. Hipfinger, S.J. Advani, J. Li, O.F. Khan, A. Franovic, S.M. Weis, S. Kumar, L.M. Coussens, D.G. Anderson, C.C. Chen, D.A. Cheresh, S. Anand, MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment. Nat. Commun. 7, 13597 (2016)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. K. Gupta, R. Metgud, J. Gupta, Evaluation of stromal myofibroblasts in oral leukoplakia, oral submucous fibrosis, and oral squamous cell carcinoma - an immunohistochemical study. J. Cancer Res. Ther. 11, 893–898 (2015)

    Article  PubMed  CAS  Google Scholar 

  126. M. Chaudhary, A.R. Gadbail, G. Vidhale, M.P. Mankar, S.M. Gondivkar, M. Gawande, S. Patil, Comparison of myofibroblasts expression in oral squamous cell carcinoma, verrucous carcinoma, high risk epithelial dysplasia, low risk epithelial dysplasia and normal oral mucosa. Head Neck Pathol. 6, 305–313 (2012)

    Article  PubMed  PubMed Central  Google Scholar 

  127. M. Mehdipour, M. Shahidi, S. Manifar, S. Jafari, F. Mashhadi Abbas, M. Barati, H. Mortazavi, M. Shirkhoda, A. Farzanegan, Z. Elmi Rankohi, Diagnostic and prognostic relevance of salivary microRNA-21, −125a, −31 and -200a levels in patients with oral lichen planus - a short report. Cell. Oncol. 41, 329–334 (2018)

    Article  CAS  Google Scholar 

  128. R. Tamamura, H. Nagatsuka, C.H. Siar, N. Katase, I. Naito, Y. Sado, N. Nagai, Comparative analysis of basal lamina type IV collagen α chains, matrix metalloproteinases-2 and -9 expressions in oral dysplasia and invasive carcinoma. Acta Histochem. 115, 113–119 (2013)

    Article  PubMed  CAS  Google Scholar 

  129. H.-X. Fan, H.-X. Li, D. Chen, Z.-X. Gao, J.-H. Zheng, Changes in the expression of MMP2, MMP9, and ColIV in stromal cells in oral squamous tongue cell carcinoma: Relationships and prognostic implications. J. Exp. Clin. Cancer Res. 31, 90 (2012)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. P. Le Bars, P. Piloquet, A. Daniel, B. Giumelli, Immunohistochemical localization of type IV collagen and laminin (alpha1) in denture stomatitis. J. Oral Pathol. Med. 30, 98–103 (2001)

    Article  PubMed  Google Scholar 

  131. F.B. Galateau-Salle, R.E. Luna, K. Horiba, M.N. Sheppard, T. Hayashi, M.V. Fleming, T.V. Colby, W. Bennett, C.C. Harris, W.G. Stetler-Stevenson, L. Liotta, V.J. Ferrans, W.D. Travis, Matrix metalloproteinases and tissue inhibitors of metalloproteinases in bronchial squamous preinvasive lesions. Hum. Pathol. 31, 296–305 (2000)

    Article  PubMed  CAS  Google Scholar 

  132. M. Sathyakumar, G. Sriram, T.R. Saraswathi, B. Sivapathasundharam, Immunohistochemical evaluation of mast cells and vascular endothelial proliferation in oral precancerous lesion-leukoplakia. J. Oral Maxillofac. Pathol. 16, 343–348 (2012)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. S. Ramsridhar, M. Narasimhan, Immunohistochemical evaluation of mast cells in leukoplakia and oral squamous cell carcinoma. J. Clin. Diagn. Res. 10, ZC100–ZC103 (2016)

    PubMed  PubMed Central  CAS  Google Scholar 

  134. M. Kinra, K. Ramalingam, A. Sarkar, F. Rehman, K.L. Girish, Comparison of mast cell count and mast cell density in normal mucosa, oral leukoplakia, oral lichen planus, oral submucous fibrosis and oral squamous cell carcinoma–a study on 50cases. JPSI 1, 4–11 (2012)

    Google Scholar 

  135. S. Nayak, M.M. Goel, A. Makker, V. Bhatia, S. Chandra, S. Kumar, S.P. Agarwal, Fibroblast growth factor (FGF-2) and its receptors FGFR-2 and FGFR-3 may be putative biomarkers of malignant transformation of potentially malignant oral lesions into oral squamous cell carcinoma. PLoS One 10, e0138801 (2015)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. P.A. Kenny, M.J. Bissell, Tumor reversion: Correction of malignant behavior by microenvironmental cues. Int. J. Cancer 107, 688–695 (2003)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. S.P. Kerkar, N.P. Restifo, Cellular constituents of immune escape within the tumor microenvironment. Cancer Res. 72, 3125–3130 (2012)

    Article  PubMed  CAS  Google Scholar 

  138. H. Qin, C. Zhao, Y. Sun, J. Ren, X. Qu, Metallo-supramolecular complexes enantioselectively eradicate cancer stem cells in vivo. J. Am. Chem. Soc. 139, 16201–16209 (2017)

    Article  PubMed  CAS  Google Scholar 

  139. V. Pautu, D. Leonetti, E. Lepeltier, N. Clere, C. Passirani, Nanomedicine as a potent strategy in melanoma tumor microenvironment. Pharmacol. Res. 126, 31–53 (2017)

    Article  PubMed  CAS  Google Scholar 

  140. G. Valenti, H.M. Quinn, G.J.J.E. Heynen, L. Lan, J.D. Holland, R. Vogel, A. Wulf-Goldenberg, W. Birchmeier, Cancer stem cells regulate cancer-associated fibroblasts via activation of hedgehog signaling in mammary gland tumors. Cancer Res. 77, 2134–2147 (2017)

    Article  PubMed  CAS  Google Scholar 

  141. C. Zang, J. Eucker, P. Habbel, C. Neumann, C.-O. Schulz, N. Bangemann, L. Kissner, H. Riess, H. Liu, Targeting multiple tyrosine kinase receptors with Dovitinib blocks invasion and the interaction between tumor cells and cancer-associated fibroblasts in breast cancer. Cell Cycle 14, 1291–1299 (2015)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. F. Mpekris, P. Papageorgis, C. Polydorou, C. Voutouri, M. Kalli, A.P. Pirentis, T. Stylianopoulos, Sonic-hedgehog pathway inhibition normalizes desmoplastic tumor microenvironment to improve chemo- and nanotherapy. J. Control. Release 261, 105–112 (2017)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Y. Du, Q. Long, L.I.N. Zhang, Y. Shi, X. Liu, X. Li, B.I.N. Guan, Y. Tian, X. Wang, L.E.I. Li, D. He, Curcumin inhibits cancer-associated fibroblast-driven prostate cancer invasion through MAOA/mTOR/HIF-1α signaling. Int. J. Oncol. 47, 2064–2072 (2015)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. K. Li, H. Kang, Y. Wang, T. Hai, G. Rong, H. Sun, Letrozole-induced functional changes in carcinoma-associated fibroblasts and their influence on breast cancer cell biology. Med. Oncol. 33, 64 (2016)

    Article  PubMed  CAS  Google Scholar 

  145. K.P.L. Fabian, N. Chi-Sabins, J.L. Taylor, R. Fecek, A. Weinstein, W.J. Storkus, Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice. Oncoimmunology 6, e1290035 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  146. C. Wang, Y. Li, H. Chen, J. Zhang, J. Zhang, T. Qin, C. Duan, X. Chen, Y. Liu, X. Zhou, J. Yang, Inhibition of CYP4A by a novel flavonoid FLA-16 prolongs survival and normalizes tumor vasculature in glioma. Cancer Lett. 402, 131–141 (2017)

    Article  PubMed  CAS  Google Scholar 

  147. Q. Zhou, Y. Zhou, X. Liu, Y. Shen, GDC-0449 improves the antitumor activity of nano-doxorubicin in pancreatic cancer in a fibroblast-enriched microenvironment. Sci. Rep. 7, 13379 (2017)

  148. C.J. Hanley, M. Mellone, K. Ford, S.M. Thirdborough, T. Mellows, S.J. Frampton, D.M. Smith, E. Harden, C. Szyndralewiez, M. Bullock, F. Noble, K.A. Moutasim, E.V. King, P. Vijayanand, A.H. Mirnezami, T.J. Underwood, C.H. Ottensmeier, G.J. Thomas, Targeting the myofibroblastic cancer-associated fibroblast phenotype through inhibition of NOX4. J. Natl. Cancer Inst. 110, 109–120 (2018). https://doi.org/10.1093/jnci/djx121

    Article  Google Scholar 

  149. M. Gabasa, R. Ikemori, F. Hilberg, N. Reguart, J. Alcaraz, Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patients. Br. J. Cancer 117, 1128–1138 (2017)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Y. Wei, T.J. Kim, D.H. Peng, D. Duan, D.L. Gibbons, M. Yamauchi, J.R. Jackson, C.J. Le Saux, C. Calhoun, J. Peters, R. Derynck, B.J. Backes, H.A. Chapman, Fibroblast-specific inhibition of TGF-β1 signaling attenuates lung and tumor fibrosis. J. Clin. Invest. 127, 3675–3688 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  151. M. Chen, X. Lei, C. Shi, M. Huang, X. Li, B. Wu, Z. Li, W. Han, B. Du, J. Hu, Q. Nie, W. Mai, N. Ma, N. Xu, X. Zhang, C. Fan, A. Hong, M. Xia, L. Luo, A. Ma, H. Li, Q. Yu, H. Chen, D. Zhang, W. Ye, Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents. J. Clin. Invest. 127, 3689–3701 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors acknowledge financial support from DST-SERB, Government of India, New Delhi, India (SERB/LS-1028/2013) and Dr. D.Y. Patil Vidyapeeth, Pune, India (DPU/05/01/2016).

Funding

This study was funded by DST-SERB, Government of India, New Delhi, India (SERB/LS-1028/2013) and Dr. D.Y. Patil Vidyapeeth, Pune, India (DPU/05/01/2016).

Author information

Authors and Affiliations

  1. Cancer and Translational Research Lab, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, 411033, India

    Pritish Nilendu, Devashree Jahagirdar, Ishita Tandon, Jayanta K. Pal & Nilesh Kumar Sharma

  2. Department of Oral Pathology and Microbiology, Dr. D Y Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, India

    Sachin C. Sarode & Gargi S. Sarode

  3. Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Jazan, Saudi Arabia

    Shankargouda Patil

Authors
  1. Pritish Nilendu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sachin C. Sarode
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Devashree Jahagirdar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ishita Tandon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shankargouda Patil
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gargi S. Sarode
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jayanta K. Pal
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nilesh Kumar Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Sachin C. Sarode or Nilesh Kumar Sharma.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

Ethical approval for this study is not required.

Informed consent

Informed consent for this study is not required.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nilendu, P., Sarode, S.C., Jahagirdar, D. et al. Mutual concessions and compromises between stromal cells and cancer cells: driving tumor development and drug resistance. Cell Oncol. 41, 353–367 (2018). https://doi.org/10.1007/s13402-018-0388-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-018-0388-2

Keywords

Search

Navigation