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Intercellular Interactions in the Tumor Stroma and Their Role in Oncogenesis

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Abstract

Cancer remains the second leading cause of death in the world, despite significant improvements that have been made in diagnosis and therapy. This is partly due to the fact that most of the therapeutic agents that have been developed target tumor cells and ignore the tumor microenvironment. Currently, there is an increased interest in understanding the role of the microenvironment in tumor growth and progression, which has prompted a new paradigm of cancer treatment: targeting the tumor stroma. The stroma can make up more than 50% of the tumor node mass and coordinate proliferation, local invasion, and eventually metastasis of cancer cells into surrounding tissues. The stroma includes an extracellular matrix, immune cells, tumor vascular network, fibroblasts, neuroendocrine cells, and fat cells. Malignant cells recruit stromal cells to remodel the tissue structure and isolate growth stimuli and intermediate metabolites. As a result, stromal components contribute to multiple processes of oncogenesis, which include tumor growth, invasion, metastasis, and resistance to therapy. Cancer-associated fibroblasts play an important role in these processes. This review examines the main mechanisms of intercellular interactions in the tumor stroma, including their regulation and role in oncogenesis.

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REFERENCES

  1. Pietras, K. and Ostman, A., Hallmarks of cancer: Interactions with the tumor stroma, Exp. Cell Res., 2010, vol. 316, no. 8, pp. 1324–1331. https://doi.org/10.1016/j.yexcr.2010.02.045

    Article  CAS  PubMed  Google Scholar 

  2. Quail, D.F. and Joyce, J.A., Microenvironmental regulation of tumor progression and metastasis, Nat. Med., 2013, vol. 19, no. 11, pp. 1423–1437. https://doi.org/10.1038/nm.3394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Vong, S. and Kalluri, R., The role of stromal myofibroblast and extracellular matrix in tumor angiogenesis, Genes Cancer, 2011, vol. 2, no. 12, pp. 1139–1145. https://doi.org/10.1177/1947601911423940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Balkwill, F.R., Capasso, M., and Hagemann, T., The tumor microenvironment at a glance, J. Cell Sci., 2012, vol. 125, part 23, pp. 5591–5596. https://doi.org/10.1242/jcs.116392

    Article  CAS  PubMed  Google Scholar 

  5. Hinshaw, D.C. and Shevde, L.A., The tumor microenvironment innately modulates cancer progression, Cancer Res., 2019, vol. 79, no. 18, pp. 4557–4566. https://doi.org/10.1158/0008-5472.CAN-18-3962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yuan, Y., Jiang, Y.C., Sun, C.K., and Chen, Q.M., Role of the tumor microenvironment in tumor progression and the clinical applications, Oncol. Rep., 2016, vol. 35, no. 5, pp. 2499–2515. https://doi.org/10.3892/or.2016.4660

    Article  CAS  PubMed  Google Scholar 

  7. Chen, Y., McAndrews, K.M., and Kalluri, R., Clinical and therapeutic relevance of cancer-associated fibroblasts, Nat. Rev. Clin. Oncol., 2021, vol. 18, no. 12, pp. 792–804. https://doi.org/10.1038/s41571-021-00546-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hui, L. and Chen, Y., Tumor microenvironment: Sanctuary of the devil, Cancer Lett., 2015, vol. 368, no. 1, pp. 7–13. https://doi.org/10.1016/j.canlet.2015.07.039

    Article  CAS  PubMed  Google Scholar 

  9. Gajewski, T.F., Schreiber, H., and Fu, Y.-X., Innate and adaptive immune cells in the tumor microenvironment, Nat. Immunol., 2013, vol. 14, no. 10, pp. 1014–1022. https://doi.org/10.1038/ni.2703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Petty, A.J. and Yang, Y., Tumor-associated macrophages: implications in cancer immunotherapy, Immunotherapy, 2017, vol. 9, no. 3, pp. 289–302. https://doi.org/10.2217/imt-2016-0135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang, D., Zheng, Y., Lin, Z., Liu, X., Li, J., Yang, H., et al., Equipping natural killer cells with specific targeting and checkpoint blocking for enhanced adoptive immunotherapy in solid tumors, Angew. Chem. Int. Ed., 2020, vol. 59, no. 29, pp. 12022–12028. https://doi.org/10.1002/anie.202002145

    Article  CAS  Google Scholar 

  12. Ruscetti, M., Morris, J.P., Mezzadra, R., Russell, J., Leibold, J., Romesser, P.B., et al., Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer, Cell, 2020, vol. 181, no. 2, pp. 424–441. https://doi.org/10.1016/j.cell.2020.03.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Viallard, C. and Larrivée, B., Tumor angiogenesis and vascular normalization: Alternative therapeutic targets, Angiogenesis, 2017, vol. 20, no. 4, pp. 409–426. https://doi.org/10.1007/s10456-017-9562-9

    Article  CAS  PubMed  Google Scholar 

  14. Eble, J.A. and Niland, S., The extracellular matrix in tumor progression and metastasis, Clin. Exp. Metastasis, 2019, vol. 36, no. 3, pp. 171–198. https://doi.org/10.1007/s10585-019-09966-1

    Article  CAS  PubMed  Google Scholar 

  15. Girard, C.A., Lecacheur, M., Ben Jouira, R., Berestjuk, I., Diazzi, S., Prod’homme, V., et al., A feed-forward mechanosignaling loop confers resistance to therapies targeting the MAPK pathway in BRAF-mutant melanoma, Cancer Res., 2020, vol. 80, no. 10, pp. 1927–1941. https://doi.org/10.1158/0008-5472.CAN-19-2914

    Article  CAS  PubMed  Google Scholar 

  16. Gerarduzzi, C., Hartmann, U., Leask, A., and Drobetsky, E., The matrix revolution: Matricellular proteins and restructuring of the cancer microenvironment, Cancer Res., 2020, vol. 80, no. 13, pp. 2705–2717. https://doi.org/10.1158/0008-5472.CAN-18-2098

    Article  CAS  PubMed  Google Scholar 

  17. Castells, M., Thibault, B., Delord, J.-.P., and Couderc, B., Implication of tumor microenvironment in chemoresistance: tumor-associated stromal cells protect tumor cells from cell death, Int. J. Mol. Sci., 2012, vol. 13, no. 8, pp. 9545–9571. https://doi.org/10.3390/ijms13089545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kalluri, R. and Zeisberg, M., Fibroblasts in cancer, Nat. Rev. Cancer, 2006, vol. 6, no. 5, pp. 392–401. https://doi.org/10.1038/nrc1877

    Article  CAS  PubMed  Google Scholar 

  19. Ravikanth, M., Manjunath, K., Ramachandran, C.R., Soujanya, P., and Saraswathi, T.R., Heterogenecity of fibroblasts, J. Oral Maxillofac. Pathol., 2011, vol. 15, no. 2, pp. 247–250. https://doi.org/10.4103/0973-029X.84516

    Article  PubMed  PubMed Central  Google Scholar 

  20. des Jardins-Park, H.E., Foster, D.S., and Longaker, M.T., Fibroblasts and wound healing: An update, Regener. Med., 2018, vol. 13, no. 5, pp. 491–495. https://doi.org/10.2217/rme-2018-0073

    Article  CAS  Google Scholar 

  21. Desmouliere, A., Darby, I.A., Laverdet, B., and Bonté, F., Fibroblasts and myofibroblasts in wound healing, Clin., Cosmet. Invest. Dermatol., 2014, vol. 7, pp. 301–311. https://doi.org/10.2147/CCID.S50046

    Article  Google Scholar 

  22. Liu, T., Zhou, L., Li, D., Andl, T., and Zhang, Y., Cancer-associated fibroblasts build and secure the tumor microenvironment, Front. Cell Dev. Biol., 2019, vol. 7, pp. 1–14. https://doi.org/10.3389/fcell.2019.00060

    Article  Google Scholar 

  23. Sahai, E., Astsaturov, I., Cukierman, E., DeNardo, D.G., Egeblad, M., Evans, R.M., et al., A frame work for advancing our understanding of cancer-associated fibroblasts, Nat. Rev. Cancer, 2020, vol. 20, no. 3, pp. 174–186. https://doi.org/10.1038/s41568-019-0238-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Santi, A., Kugeratski, F.G., and Zanivan, S., Cancer associated fibroblasts: The architects of stroma remodeling, Proteomics, 2018, vol. 18, nos. 5–6, p. e1700167. https://doi.org/10.1002/pmic.201700167

    Article  CAS  PubMed  Google Scholar 

  25. Wang, F.T., Sun, W., Zhang, J.T., and Fan, Y.Z., Cancer-associated fibroblast regulation of tumor neo-angiogenesis as a therapeutic target in cancer, Oncol. Lett., 2019, vol. 17, no. 3, pp. 3055–3065. https://doi.org/10.3892/ol.2019.9973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Monteran, L. and Erez, N., The dark side of fibroblasts: Cancer-associated fibroblasts as mediators of immunosuppression in the tumor microenvironment, Front. Immunol., 2019, vol. 10, p. 1835. https://doi.org/10.3389/fimmu.2019.01835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lim, H. and Moon, A., Inflammatory fibroblasts in cancer, Arch. Pharmacal Res., 2016, vol. 39, no. 8, pp. 1021–1031. https://doi.org/10.1007/s12272-016-0787-8

    Article  CAS  Google Scholar 

  28. Labernadie, A., Kato, T., Brugués, A., Serra-Picamal, X., Derzsi, S., Arwert, E., et al., A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion, Nat. Cell Biol., 2017, vol. 19, no. 3, pp. 224–237. https://doi.org/10.1038/ncb3478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen, W.-J., Ho, C.-C., Chang, Y.-L., Chen, H.-Y., Lin, C.-A., Ling, T.-Y., et al., Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signaling, Nat. Commun., 2014, vol. 5, pp. 1–17. https://doi.org/10.1038/ncomms4472

    Article  CAS  Google Scholar 

  30. Nikolopoulou, P.A., Koufaki, M.A., and Kostourou, V., The adhesome network: Key components shaping the tumour stroma, Cancers (Basel), 2021, vol. 13, no. 3, p. 525. https://doi.org/10.3390/cancers13030525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Han, L., Lam, E.W.-F., and Sun, Y., Extracellular vesicles in the tumor microenvironment: Old stories, but new tales, Mol. Cancer, 2019, vol. 18, no. 1, p. 59. https://doi.org/10.1186/s12943-019-0980-8

    Article  PubMed  PubMed Central  Google Scholar 

  32. Zhang, D.X., Vu, L.T., Ismail, N.N., Le, M.T.N., and Grimson, A., Landscape of extracellular vesicles in the tumour microenvironment: Interactions with stromal cells and with non-cell components, and impacts on metabolic reprogramming, horizontal transfer of neoplastic traits, and the emergence of therapeutic resistance, Semin. Cancer Biol., 2021, vol. 74, pp. 24–44. https://doi.org/10.1016/j.semcancer.2021.01.007

    Article  CAS  PubMed  Google Scholar 

  33. VanNiel, G., D’Angelo, G., and Raposo, G., Shedding light on the cell biology of extracellular vesicles, Nat. Rev. Mol. Cell Biol., 2018, vol. 19, no. 4, pp. 213–228. https://doi.org/10.1038/nrm.2017.125

    Article  CAS  Google Scholar 

  34. Xie, C., Ji, N., Tang, Z., Li, J., and Chen, Q., The role of extracellular vesicles from different origin in the microenvironment of head and neck cancers, Mol. Cancer, 2019, vol. 18, no. 1, p. 83. https://doi.org/10.1186/s12943-019-0985-3

    Article  PubMed  PubMed Central  Google Scholar 

  35. Yanez-Mo, M., Siljander, P.R., Andreu, Z., Zavec, A.B., Borras, F.E., Buzas, E.I., et al., Biological properties of extracellular vesicles and their physiological functions, J. Extracell. Vesicles, 2015, vol. 4, p. 27066. https://doi.org/10.3402/jev.v4.27066

    Article  PubMed  Google Scholar 

  36. Meldolesi, J., Exosomes and ectosomes in intercellular communication, Curr. Biol., 2018, vol. 28, no. 8, pp. 435–444. https://doi.org/10.1016/j.cub.2018.01.059

    Article  CAS  Google Scholar 

  37. Margolis, L. and Sadovsky, Y., The biology of extracellular vesicles: The known unknowns, PLoS Biol., 2019, vol. 17, no. 7, p. e3000363. https://doi.org/10.1371/journal.pbio.3000363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dai, G., Yao, X., Zhang, Y., Gu, J., Geng, Y., Xue, F., et al., Colorectal cancer cell-derived exosomes containing mir-10b regulate fibroblast cells via the pi3k/akt pathway, Bull. Cancer, 2018, vol. 105, no. 4, pp. 336–349. https://doi.org/10.1016/j.bulcan.2017.12.009

    Article  PubMed  Google Scholar 

  39. Walker, C., Mojares, E., and Hernandez, A.D.R., Role of extracellular matrix in development and cancer progression, Int. J. Mol. Sci., 2018, vol. 19, no. 10, p. 3028. https://doi.org/10.3390/ijms19103028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Naito, Y., Yamamoto, Y., Sakamoto, N., Shimomura, I., Kogure, A., Kumazaki, M., et al., Cancer extracellular vesicles contribute to stromal heterogeneity by inducing chemokines in cancer-associated fibroblasts, Oncogene, 2019, vol. 38, no. 28, pp. 5566–5579. https://doi.org/10.1038/s41388-019-0832-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hassan, M.S., Cwidak, N., Awasthi, N., and von Holzen, U., Cytokine interaction with cancer-associated fibroblasts in esophageal cancer, Cancer Control, 2022, vol. 29, p. 10732748221078470. https://doi.org/10.1177/10732748221078470

    Article  PubMed  PubMed Central  Google Scholar 

  42. Blank, S., Nienhüser, H., Dreikhausen, L., Sisic, L., Heger, U., Ott, K., et al., Inflammatory cytokines are associated with response and prognosis in patients with esophageal cancer, Oncotarget, 2017, vol. 8, no. 29, pp. 47518–47532. https://doi.org/10.18632/oncotarget.17671

    Article  PubMed  PubMed Central  Google Scholar 

  43. Bhat, A.A., Nisar, S., Maacha, S., Carneiro-Lobo, T.C., Akhtar, S., Siveen, K.S., et al., Cytokine-chemokine network driven metastasis in esophageal cancer; promising avenue for targeted therapy, Mol. Cancer, 2021, vol. 20, no. 1, p. 2. https://doi.org/10.1186/s12943-020-01294-3

    Article  PubMed  PubMed Central  Google Scholar 

  44. Hughes, C.E. and Nibbs, R.J.B., A guide to chemokines and their receptors, FEBS J., 2018, vol. 285, no. 16, pp. 2944–2971. https://doi.org/10.1111/febs.144664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Calon, A., Tauriello, D.V., and Batlle, E., TGF-beta in CAF-mediated tumor growth and metastasis, Semin. Cancer Biol., 2014, vol. 25, pp. 15–22. https://doi.org/10.1016/j.semcancer.2013.12.008

    Article  CAS  PubMed  Google Scholar 

  46. Kalluri, R. and Weinberg, R.A., The basics of epithelial-mesenchymal transition, J. Clin. Invest., 2009, vol. 119, no. 6, pp. 1420–1428. https://doi.org/10.1172/JCI39104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zidi, I., Mestiri, S., Bartegi, A., and Amor, N.B., TNF-alpha and its inhibitors in cancer, Med. Oncol., 2010, vol. 27, no. 2, pp. 185–198. https://doi.org/10.1007/s12032-009-9190-3

    Article  CAS  PubMed  Google Scholar 

  48. Zhou, Q., Wu, X., Wang, X., Yu, Z., Pan, T., Li, Z., et al., The reciprocal interaction between tumor cells and activated fibroblasts mediated by TNF-α/IL-33/ST2L signaling promotes gastric cancer metastasis, Oncogene, 2020, vol. 39, no. 7, pp. 1414–1428. https://doi.org/10.1038/s41388-019-1078-x

    Article  CAS  PubMed  Google Scholar 

  49. Masjedi, A., Hashemi, V., Hojjat-Farsangi, M., Ghalamfarsa, G., Azizi, G., Yousefi, M., et al., The significant role of interleukin-6 and it signaling pathway in the immunopathogenesis and treatment of breast cancer, Biomed. Pharmacother., 2018, vol. 108, pp. 1415–1424. https://doi.org/10.1016/j.biopha.2018.09.177

    Article  CAS  PubMed  Google Scholar 

  50. Karakasheva, T.A., Lin, E.W., Tang, Q., Qiao, E., Waldron, T.J., Soni, M., et al., IL-6 mediates crosstalk between tumor cells and activated fibroblasts in the tumor microenvironment, Cancer Res., 2018, vol. 78, no. 17, pp. 4957–4970. https://doi.org/10.1158/0008-5472.CAN-17-2268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Baggiolini, M., CXCL8—the first chemokine, Front. Immunol., 2015, vol. 6, p. 85. https://doi.org/10.3389/fimmu.2015.00285

    Article  CAS  Google Scholar 

  52. Tong, Q., Wang, X.L., Li, S.B., Yang, G.-L., Jin, S., Gaoet, Z.-Y., et al., Combined detection of IL-6 and IL-8 is beneficial to the diagnosis of early-stage esophageal squamous cell cancer: A preliminary study based on the screening of serum markers using protein chips, OncoTargets Ther., 2018, vol. 11, pp. 5777–5787. https://doi.org/10.2147/OTT.S171242

    Article  CAS  Google Scholar 

  53. Grugan, K.D., Miller, C.G., Yao, Y., Michaylira, C.Z., Ohashi, S., Klein-Szanto, A.J., et al., Fibroblast-secreted hepatocyte growth factor plays a functional role in esophageal squamous cell carcinoma invasion, Proc. Natl. Acad. Sci. U. S. A., 2010, vol. 107, no. 24, pp. 11026–11031. https://doi.org/10.1073/pnas.0914295107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Moosavi, F., Giovannetti, E., Saso, L., and Firuzi, O., HGF/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers, Crit. Rev. Clin. Lab. Sci., 2019, vol. 56, no. 8, pp. 533–566. https://doi.org/10.1080/10408363.2019.1653821

    Article  CAS  PubMed  Google Scholar 

  55. Li, Y.Y., Tao, Y.W., Gao, S., Li, P., Zheng, J.M., Zhang, S.E., et al., Cancer associated fibroblasts contribute to oral cancer cells proliferation and metastasis via exosome-mediated paracrine miR-34a-5p, eBioMedicine, 2018, vol. 36, pp. 209–220. https://doi.org/10.1016/j.ebiom.2018.09.006

    Article  PubMed  PubMed Central  Google Scholar 

  56. Vu, T.L., Peng, B., Zhang, D.X., Ma, V., Mathey-Andrews, C.A., Lam, C.K., et al., Tumor-secreted extracellular vesicles promote the activation of cancer-associated fibroblasts via the transfer of microRNA-125b, J. Extracell. Vesicles, 2019, vol. 8, no. 1, p. 1599680. https://doi.org/10.1080/20013078.2019.1599680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Donnarumma, E., Fiore, D., Nappa, M., Roscigno, G., Adamo, A., Iaboni, M., et al., Cancer-associated fibroblasts release exosomal microRNAs that dictate an aggressive phenotype in breast cancer, Oncotarget, 2017, vol. 8, no. 12, pp. 19592–19608. https://doi.org/10.18632/oncotarget.14752

    Article  PubMed  PubMed Central  Google Scholar 

  58. Quinn, J.J. and Chang, H., Unique features of long non-coding RNA biogenesis and function, Nat. Rev. Genet., 2015, vol. 17, no. 1, pp. 47–62. https://doi.org/10.1038/nrg.2015.10

    Article  CAS  Google Scholar 

  59. del Vecchio, F., Lee, G.H., Hawezi, J., Bhome, R., Pugh, S., Sayan, A.E., et al., Long non-coding RNAs within the tumour microenvironment and their role in tumour-stroma cross-talk, Cancer Lett., 2018, vol. 421, pp. 94–102. https://doi.org/10.1016/j.canlet.2018.02.022

    Article  CAS  PubMed  Google Scholar 

  60. Ahn, Y.-H. and Kim, J.S., Long non-coding RNAs as regulators of interactions between cancer-associated fibroblasts and cancer cells in the tumor microenvironment, Int. J. Mol. Sci., 2020, vol. 21, no. 20, p. 7484. https://doi.org/10.3390/ijms21207484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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    N. A. Lunina & D. R. Safina

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Lunina, N.A., Safina, D.R. Intercellular Interactions in the Tumor Stroma and Their Role in Oncogenesis. Mol. Genet. Microbiol. Virol. 37, 167–172 (2022). https://doi.org/10.3103/S0891416822040048

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