Biopolym. Cell. 2018; 34(4):271-283.
http://dx.doi.org/10.7124/bc.000980
Reviews
Cancer–stroma interactions as a target for cancer treatment.
1, 2Alekseenko I. V., 1, 2Pleshkan V. V., 1, 2Sverdlov E. D.
  1. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS
    16/10, Miklukho-Maklaya, Moscow, Russian Federation, 117997
  2. Institute of Molecular Genetics, Russian Academy of Sciences,
    2, Kurchatov Sq. Moscow Russian Federation, 123182

Abstract

During tumor evolution, cancer cells use the tumor-stroma crosstalk to reorganize the microenvironment for maximum robustness of tumor. The success of immune checkpoint therapy generates a new cancer therapy paradigm: an effective cancer treatment should not aim to influence the individual components of super complex intracellular interactomes (molecular targeting), but rather to disrupt the intercellular interactions between cancer and stromal cells, thus breaking the tumor as a whole. In this minireview we consider cancer associated fibroblasts (CAF) and their interactions with cancer cells as a promising direction for cancer therapy.
Keywords: cancer, hallmark, therapy, immunotherapy, stroma, crosstalk
Full text: (PDF, in English)

References

[1] Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57-70.
[2] Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21(3):309-22.
[3] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74.
[4] Orimo A, Weinberg RA. Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle. 2006;5(15):1597-601.
[5] Gonda TA, Varro A, Wang TC, Tycko B. Molecular biology of cancer-associated fibroblasts: can these cells be targeted in anti-cancer therapy? Semin Cell Dev Biol. 2010;21(1):2-10.
[6] De Palma M, Hanahan D. The biology of personalized cancer medicine: facing individual complexities underlying hallmark capabilities. Mol Oncol. 2012;6(2):111-27.
[7] Fouad YA, Aanei C. Revisiting the hallmarks of cancer. Am J Cancer Res. 2017;7(5):1016-36.
[8] Gascard P, Tlsty TD. Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev. 2016;30(9):1002-19.
[9] Chen F, Zhuang X, Lin L, Yu P, Wang Y, Shi Y, Hu G, Sun Y. New horizons in tumor microenvironment biology: challenges and opportunities. BMC Med. 2015;13:45.
[10] Gandellini P, Andriani F, Merlino G, D'Aiuto F, Roz L, Callari M. Complexity in the tumour microenvironment: Cancer associated fibroblast gene expression patterns identify both common and unique features of tumour-stroma crosstalk across cancer types. Semin Cancer Biol. 2015;35:96-106.
[11] Stadler M, Walter S, Walzl A, Kramer N, Unger C, Scherzer M, Unterleuthner D, Hengstschläger M, Krupitza G, Dolznig H. Increased complexity in carcinomas: Analyzing and modeling the interaction of human cancer cells with their microenvironment. Semin Cancer Biol. 2015;35:107-24.
[12] Zi F, He J, He D, Li Y, Yang L, Cai Z. Fibroblast activation protein α in tumor microenvironment: recent progression and implications (review). Mol Med Rep. 2015;11(5):3203-11.
[13] Raffaghello L, Dazzi F. Classification and biology of tumour associated stromal cells. Immunol Lett. 2015;168(2):175-82.
[14] Perrimon N, Pitsouli C, Shilo BZ. Signaling mechanisms controlling cell fate and embryonic patterning. Cold Spring Harb Perspect Biol. 2012;4(8):a005975.
[15] Bizzarri M, Cucina A. Tumor and the microenvironment: a chance to reframe the paradigm of carcinogenesis? Biomed Res Int. 2014;2014:934038.
[16] Guo F, Wang Y, Liu J, Mok SC, Xue F, Zhang W. CXCL12/CXCR4: a symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks. Oncogene. 2016;35(7):816-26.
[17] Sluka P, Davis ID. Cell mates: paracrine and stromal targets for prostate cancer therapy. Nat Rev Urol. 2013;10(8):441-51.
[18] Bhome R, Bullock MD, Al Saihati HA, Goh RW, Primrose JN, Sayan AE, Mirnezami AH. A top-down view of the tumor microenvironment: structure, cells and signaling. Front Cell Dev Biol. 2015;3:33.
[19] Weinberg RA. Coming full circle-from endless complexity to simplicity and back again. Cell. 2014;157(1):267-71.
[20] Reina-Campos M, Moscat J, Diaz-Meco M. Metabolism shapes the tumor microenvironment. Curr Opin Cell Biol. 2017;48:47-53.
[21] Bhome R, Al Saihati HA, Goh RW, Bullock MD, Primrose JN, Thomas GJ, Sayan AE, Mirnezami AH. Translational aspects in targeting the stromal tumour microenvironment: from bench to bedside. New Horiz Transl Med. 2016;3(1):9-21.
[22] Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16(9):582-98.
[23] LeBleu VS, Kalluri R. A peek into cancer-associated fibroblasts: origins, functions and translational impact. Dis Model Mech. 2018;11(4). pii: dmm029447.
[24] Valkenburg KC, de Groot AE, Pienta KJ. Targeting the tumour stroma to improve cancer therapy. Nat Rev Clin Oncol. 2018;15(6):366-381.
[25] Munhoz RR, Postow MA. Clinical development of pd-1 in advanced melanoma. Cancer J. 2018 Jan/Feb;24(1):7-14.
[26] Postow M, Wolchok J. Patient selection criteria and toxicities associated with checkpoint inhibitor immunotherapy. UptoDate. 2018.
[27] Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348(6230):56-61.
[28] Sharpe AH. Introduction to checkpoint inhibitors and cancer immunotherapy. Immunol Rev. 2017;276(1):5-8.
[29] Wilson RAM, Evans TRJ, Fraser AR, Nibbs RJB. Immune checkpoint inhibitors: new strategies to checkmate cancer. Clin Exp Immunol. 2018;191(2):133-148.
[30] Calabrese L, Velcheti V. Checkpoint immunotherapy: good for cancer therapy, bad for rheumatic diseases. Ann Rheum Dis. 2017;76(1):1-3.
[31] Abdin SM, Zaher DM, Arafa EA, Omar HA. Tackling cancer resistance by immunotherapy: updated clinical impact and safety of PD-1/PD-L1 inhibitors. Cancers (Basel). 2018;10(2). pii: E32.
[32] Postow MA, Hellmann MD. Adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(12):1165.
[33] Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med. 2018;378(2):158-168.
[34] Kuhlmann L, Cummins E, Samudio I, Kislinger T. Cell-surface proteomics for the identification of novel therapeutic targets in cancer. Expert Rev Proteomics. 2018;15(3):259-275.
[35] Kim JW, Cochran JR. Targeting ligand-receptor interactions for development of cancer therapeutics. Curr Opin Chem Biol. 2017;38:62-69.
[36] Weikl T, Asfaw M, Krobath H, Rozycki B, Lipowsky R. Adhesion of membranes via receptor–ligand complexes: Domain formation, binding cooperativity, and active processes. Soft Matter.2009; 5(17): 3213-24.
[37] Cogdill AP, Andrews MC, Wargo JA. Hallmarks of response to immune checkpoint blockade. Br J Cancer. 2017;117(1):1-7.
[38] Alexander W. The checkpoint immunotherapy revolution: what started as a trickle has become a flood, despite some daunting adverse effects; new drugs, indications, and combinations continue to emerge. P T. 2016;41(3):185-91.
[39] Madden DL. From a patient advocate's perspective: does cancer immunotherapy represent a paradigm Shift? Curr Oncol Rep.2018; 20(1): 8.
[40] Dempke WCM, Fenchel K, Uciechowski P, Dale SP. Second- and third-generation drugs for immuno-oncology treatment-The more the better? Eur J Cancer. 2017;74:55-72.
[41] Fearon DT. The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance. Cancer Immunol Res. 2014;2(3):187-93.
[42] Day D, Monjazeb AM, Sharon E, Ivy SP, Rubin EH, Rosner GL, Butler MO. From famine to feast: developing early-phase combination immunotherapy trials wisely. Clin Cancer Res. 2017;23(17):4980-4991.
[43] Santi A, Kugeratski FG, Zanivan S. Cancer associated fibroblasts: the architects of stroma remodeling. Proteomics. 2018;18(5-6):e1700167.
[44] Marsh T, Pietras K, McAllister SS. Fibroblasts as architects of cancer pathogenesis. Biochim Biophys Acta. 2013;1832(7):1070-8.
[45] Liao Z, Tan ZW, Zhu P, Tan NS. Cancer-associated fibroblasts in tumor microenvironment - accomplices in tumor malignancy. Cell Immunol. 2018 Jan 31. pii: S0008-8749(17)30222-8.
[46] Ziani L, Chouaib S, Thiery J. Alteration of the antitumor immune response by cancer-associated fibroblasts. Front Immunol. 2018;9:414.
[47] Alkasalias T, Moyano-Galceran L, Arsenian-Henriksson M, Lehti K. Fibroblasts in the tumor microenvironment: shield or spear? Int J Mol Sci. 2018;19(5). pii: E1532.
[48] De Wever O, Van Bockstal M, Mareel M, Hendrix A, Bracke M. Carcinoma-associated fibroblasts provide operational flexibility in metastasis. Semin Cancer Biol. 2014;25:33-46.
[49] Heneberg P. Paracrine tumor signaling induces transdifferentiation of surrounding fibroblasts. Crit Rev Oncol Hematol. 2016;97:303-11.
[50] Augsten M. Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment. Front Oncol. 2014;4:62.
[51] Tao L, Huang G, Song H, Chen Y, Chen L. Cancer associated fibroblasts: An essential role in the tumor microenvironment. Oncol Lett. 2017;14(3):2611-2620.
[52] Lamprecht S, Sigal-Batikoff I, Shany S, Abu-Freha N, Ling E, Delinasios GJ, Moyal-Atias K, Delinasios JG, Fich A. Teaming up for trouble: cancer cells, transforming growth factor-β1 signaling and the epigenetic corruption of stromal naïve fibroblasts. cancers (Basel). 2018;10(3). pii: E61.
[53] Du H, Che G. Genetic alterations and epigenetic alterations of cancer-associated fibroblasts. Oncol Lett. 2017;13(1):3-12.
[54] Belli C, Trapani D, Viale G, D'Amico P, Duso BA, Della Vigna P, Orsi F, Curigliano G. Targeting the microenvironment in solid tumors. Cancer Treat Rev. 2018;65:22-32.
[55] Harper J, Sainson RC. Regulation of the anti-tumour immune response by cancer-associated fibroblasts. Semin Cancer Biol. 2014;25:69-77.
[56] Lakins MA, Ghorani E, Munir H, Martins CP, Shields JD. Cancer-associated fibroblasts induce antigen-specific deletion of CD8 (+) T Cells to protect tumour cells. Nat Commun. 2018;9(1):948.
[57] Rozali EN, Hato SV, Robinson BW, Lake RA, Lesterhuis WJ. Programmed death ligand 2 in cancer-induced immune suppression. Clin Dev Immunol. 2012;2012:656340.
[58] Nazareth MR, Broderick L, Simpson-Abelson MR, Kelleher RJ Jr, Yokota SJ, Bankert RB. Characterization of human lung tumor-associated fibroblasts and their ability to modulate the activation of tumor-associated T cells. J Immunol. 2007;178(9):5552-62.
[59] Jacobs J, Smits E, Lardon F, Pauwels P, Deschoolmeester V. Immune checkpoint modulation in colorectal cancer: what's new and what to expect. J Immunol Res. 2015;2015:158038.
[60] Gaggioli C, Hooper S, Hidalgo-Carcedo C, Grosse R, Marshall JF, Harrington K, Sahai E. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat Cell Biol. 2007;9(12):1392-400.
[61] Semba S, Kodama Y, Ohnuma K, Mizuuchi E, Masuda R, Yashiro M, Hirakawa K, Yokozaki H. Direct cancer-stromal interaction increases fibroblast proliferation and enhances invasive properties of scirrhous-type gastric carcinoma cells. Br J Cancer. 2009;101(8):1365-73.
[62] Choe C, Shin YS, Kim SH, Jeon MJ, Choi SJ, Lee J, Kim J. Tumor-stromal interactions with direct cell contacts enhance motility of non-small cell lung cancer cells through the hedgehog signaling pathway. Anticancer Res. 2013;33(9):3715-23.
[63] He XJ, Tao HQ, Hu ZM, Ma YY, Xu J, Wang HJ, Xia YJ, Li L, Fei BY, Li YQ, Chen JZ. Expression of galectin-1 in carcinoma-associated fibroblasts promotes gastric cancer cell invasion through upregulation of integrin β1. Cancer Sci. 2014;105(11):1402-10.
[64] Yamaguchi H, Sakai R. Direct interaction between carcinoma cells and cancer associated fibroblasts for the regulation of cancer invasion. Cancers (Basel). 2015;7(4):2054-62.
[65] Labernadie A, Kato T, Brugués A, Serra-Picamal X, Derzsi S, Arwert E, Weston A, González-Tarragó V, Elosegui-Artola A, Albertazzi L, Alcaraz J, Roca-Cusachs P, Sahai E, Trepat X. A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion. Nat Cell Biol. 2017;19(3):224-237.
[66] Theveneau E, Linker C. Leaders in collective migration: are front cells really endowed with a particular set of skills? F1000Res. 2017;6:1899.
[67] Wang B. Cancer cells exploit the Eph-ephrin system to promote invasion and metastasis: tales of unwitting partners. Sci Signal. 2011;4(175):pe28.
[68] Castells M, Thibault B, Delord JP, Couderc B. Implication of tumor microenvironment in chemoresistance: tumor-associated stromal cells protect tumor cells from cell death. Int J Mol Sci. 2012;13(8):9545-71.
[69] Harrison EB, Azam SH, Pecot CV. Targeting Accessories to the crime: nanoparticle nucleic acid delivery to the tumor microenvironment. Front Pharmacol. 2018;9:307.
[70] Miao L, Liu Q, Lin CM, Luo C, Wang Y, Liu L, Yin W, Hu S, Kim WY, Huang L. Targeting tumor-associated fibroblasts for therapeutic delivery in desmoplastic tumors. Cancer Res. 2017;77(3):719-731.