Biochemistry (Moscow)

, Volume 84, Issue 9, pp 1028–1039 | Cite as

Cancer Stem Complex, Not a Cancer Stem Cell, Is the Driver of Cancer Evolution

  • E. D. Sverdlov
  • I. P. ChernovEmail author


Here, we put forward the hypothesis on the mechanism of functioning of cancer stem cells, provided that they exist. The hypothesis is based on the following postulates. 1) Paracrine exchange between cancer and stromal cells is efficient only if they are in a close contact and form a synapse-like cleft between them for the cell–cell crosstalk. The concentration of paracrine signaling molecules in the cleft is high because of the cleft small volume. 2) Cancer stem cells per se do not exist. Instead, there are cancer stem complexes formed by cancer cells tightly bound to stromal cells (portable niches) that exchange paracrine signals. 3) Cancer stem complex is a complex system with newly emerged properties, such as a stemness and resistance to external impacts, including therapeutic interventions. 4) The stemness manifests itself as the ability of cancer cells within the complex to divide asymmetrically: one daughter cell remains in the complex forming a renewed stem complex, whereas the other daughter cell detaches from the complex and transforms in a non-stem cell capable of differentiation. 5) An increased resistance of a cancer stem complex is due to the integration of its intrinsic defense systems through the exchange of paracrine signals, i.e., represents a microresistance at the cell level. 6) Cancer stem complexes can stochastically dissociate with the formation of non-stem cancer cells. Partially differentiated non-stem cancer cells are able to stochastically bind to the stromal component, dedifferentiate under the action of paracrine signals, and form new cancer stem complexes. Therefore, a tumor is a flexible system existing in the pseudo-equilibrium state. Such systems comply with the Le Chatelier’s principle stating that an equilibrium system under the action of external factors activates the processes antagonistic to the changes (homeostasis). This promotes tumor resistance at the level of cell populations, i.e., the macroresistance. 7) The portable niche travels with the cancer cell during metastasis. We propose a general therapeutic strategy targeting the contacts between cancer and stromal cells. The disruption of these contacts should lead to the destruction of cancer stem complexes and elimination of tumors.


tumorigenesis metastasis differentiation and dedifferentiation stemness stem cell niche self-renewal synapse paracrine crosstalk 



cancer-associated fibroblast


cancer stem cell


cancer stem complex


stem cell


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Funding. The work was supported by the Russian Science Foundation (project no. 19-15-00317).

Ethical norm compliance. This article does not contain description of studies with animals or human participants performed by any of the authors.


  1. 1.
    Greaves, M., and Maley, C. C. (2012) Clonal evolution in cancer, Nature, 481, 306–313, doi: Scholar
  2. 2.
    Marusyk, A., and Polyak, K. (2013) Cancer cell pheno-types, in fifty shades of grey, Science, 339, 528–529, doi: Scholar
  3. 3.
    O’Connor, M. L., Xiang, D., Shigdar, S., Macdonald, J., Li, Y., Wang, T., Pu, C., Wang, Z., Qiao, L., and Duan, W. (2014) Cancer stem cells: a contentious hypothesis now moving forward, Cancer Lett., 344, 180–187, doi: Scholar
  4. 4.
    Kreso, A., and Dick, J. E. (2014) Evolution of the cancer stem cell model, Cell Stem Cell, 14, 275–291, doi: Scholar
  5. 5.
    Valent, P., Bonnet, D., De Maria, R., Lapidot, T., Copland, M., Melo, J. V., Chomienne, C., Ishikawa, F., Schuringa, J. J., Stassi, G., Huntly, B., Herrmann, H., Soulier, J., Roesch, A., Schuurhuis, G. J., Wohrer, S., Arock, M., Zuber, J., Cerny-Reiterer, S., Johnsen, H. E., Andreeff, M., and Eaves, C. (2012) Cancer stem cell definitions and terminology: the devil is in the details, Nat. Rev. Cancer, 12, 767–775, doi: Scholar
  6. 6.
    Maenhaut, C., Dumont, J. E., Roger, P. P., and van Staveren, W. C. (2010) Cancer stem cells: a reality, a myth, a fuzzy concept or a misnomer? An analysis, Carcinogenesis, 31, 149–158, doi: Scholar
  7. 7.
    Afify, S. M., and Seno, M. (2019) Conversion of stem cells to cancer stem cells: undercurrent of cancer initiation, Cancers (Basel), 11, E345, doi: Scholar
  8. 8.
    Teng, Y. D., Wang, L., Kabatas, S., Ulrich, H., and Zafonte, R. D. (2018) Cancer stem cells or tumor survival cells? Stem Cells Dev., 27, 1466–1478, doi: Scholar
  9. 9.
    Laplane, L., and Solary, E. (2019) Towards a classification of stem cells, Elife, 8, e46563, doi: Scholar
  10. 10.
    Hermann, P. C., and Sainz, B., Jr. (2018) Pancreatic cancer stem cells: a state or an entity? Semin. Cancer Biol., 53, 223–231, doi: Scholar
  11. 11.
    Najafi, M., Farhood, B., and Mortezaee, K. (2019) Cancer stem cells (CSCs) in cancer progression and therapy, J. Cell. Physiol., 234, 8381–8395, doi: Scholar
  12. 12.
    Prager, B. C., Xie, Q., Bao, S., and Rich, J. N. (2019) Cancer stem cells: the architects of the tumor ecosystem, Cell Stem Cell, 24, 41–53, doi: Scholar
  13. 13.
    Melzer, C., von der Ohe, J., Lehnert, H., Ungefroren, H., and Hass, R. (2017) Cancer stem cell niche models and contribution by mesenchymal stroma/stem cells, Mol. Cancer, 16, 28, doi: Scholar
  14. 14.
    Kusoglu, A., and Biray Avci, C. (2019) Cancer stem cells: a brief review of the current status, Gene, 681, 80–85, doi: Scholar
  15. 15.
    Bocci, F., Gearhart-Serna, L., Boareto, M., Ribeiro, M., Ben-Jacob, E., Devi, G. R., Levine, H., Onuchic, J. N., and Jolly, M. K. (2019) Toward understanding cancer stem cell heterogeneity in the tumor microenvironment, Proc. Natl. Acad. Sci. USA, 116, 148–157, doi: Scholar
  16. 16.
    Ayob, A. Z., and Ramasamy, T. S. (2018) Cancer stem cells as key drivers of tumour progression, J. Biomed. Sci., 25, 20, doi: Scholar
  17. 17.
    Alguacil-Nunez, C., Ferrer-Ortiz, I., Garcia-Verdu, E., Lopez-Pirez, P., Llorente-Cortijo, I. M., and Sainz, B., Jr. (2018) Current perspectives on the crosstalk between lung cancer stem cells and cancer-associated fibroblasts, Crit. Rev. Oncol. Hematol., 125, 102–110, doi: Scholar
  18. 18.
    Peitzsch, C., Tyutyunnykova, A., Pantel, K., and Dubrovska, A. (2017) Cancer stem cells: the root of tumor recurrence and metastases, Semin. Cancer Biol., 44, 10–24, doi: Scholar
  19. 19.
    Vinogradova, T. V., Chernov, I. P., Monastyrskaya, G. S., Kondratyeva, L. G., and Sverdlov, E. D. (2015) Cancer stem sells: plasticity works against therapy, Acta Naturae, 7, 46–55.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Aponte, P. M., and Caicedo, A. (2017) Stemness in cancer: stem cells, cancer stem cells, and their microenvironment, Stem Cells Int., 2017, 5619472, doi: Scholar
  21. 21.
    Luo, J., Zhou, X., and Yakisich, J. S. (2014) Stemness and plasticity of lung cancer cells: paving the road for better therapy, Onco. Targets Ther., 7, 1129–1134, doi: Scholar
  22. 22.
    Shackleton, M., Quintana, E., Fearon, E. R., and Morrison, S. J. (2009) Heterogeneity in cancer: cancer stem cells versus clonal evolution, Cell, 138, 822–829, doi: Scholar
  23. 23.
    La Porta, C. A. M., and Zapperi, S. (2017) Complexity in cancer stem cells and tumor evolution: toward precision medicine, Semin. Cancer Biol., 44, 3–9, doi: Scholar
  24. 24.
    Batlle, E., and Clevers, H. (2017) Cancer stem cells revisited, Nat. Med., 23, 1124–1134, doi: Scholar
  25. 25.
    Xie, X., Teknos, T. N., and Pan, Q. (2014) Are all cancer stem cells created equal? Stem Cells Transl. Med., 3, 1111–1115, doi: Scholar
  26. 26.
    Cabrera, M. C., Hollingsworth, R. E., and Hurt, E. M. (2015) Cancer stem cell plasticity and tumor hierarchy, World J. Stem Cells, 7, 27–36, doi: Scholar
  27. 27.
    Li, Y., and Laterra, J. (2012) Cancer stem cells: distinct entities or dynamically regulated phenotypes? Cancer Res., 72, 576–580, doi: Scholar
  28. 28.
    Chaffer, C. L., and Weinberg, R. A. (2015) How does multistep tumorigenesis really proceed? Cancer Discov., 5, 22–24, doi: Scholar
  29. 29.
    Vermeulen, L., and Snippert, H. J. (2014) Stem cell dynamics in homeostasis and cancer of the intestine, Nat. Rev. Cancer, 14, 468–480, doi: Scholar
  30. 30.
    Pennings, S., Liu, K. J., and Qian, H. (2018) The stem cell niche: interactions between stem cells and their environment, Stem Cells Int., 2018, 4879379, doi: Scholar
  31. 31.
    White, A. C., and Lowry, W. E. (2015) Refining the role for adult stem cells as cancer cells of origin, Trends Cell Biol., 25, 11–20, doi: Scholar
  32. 32.
    Plaks, V., Kong, N., and Werb, Z. (2015) The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell, 16, 225–238, doi: Scholar
  33. 33.
    Ye, J., Wu, D., Wu, P., Chen, Z., and Huang, J. (2014) The cancer stem cell niche: cross talk between cancer stem cells and their microenvironment, Tumour Biol., 35, 3945–3951, doi: Scholar
  34. 34.
    Scadden, D. T. (2014) Nice neighborhood: emerging concepts of the stem cell niche, Cell, 157, 41–50, doi: Scholar
  35. 35.
    Borovski, T., De Sousa, E. M. F., Vermeulen, L., and Medema, J. P. (2011) Cancer stem cell niche: the place to be, Cancer Res., 71, 634–639, doi: Scholar
  36. 36.
  37. 37.
    Gascard, P., and Tlsty, T. D. (2016) Carcinoma-associated fibroblasts: orchestrating the composition of malignancy, Genes Dev., 30, 1002–1019, doi: Scholar
  38. 38.
    Hanahan, D., and Coussens, L. M. (2012) Accessories to the crime: functions of cells recruited to the tumor microenvironment, Cancer Cell, 21, 309–322, doi: Scholar
  39. 39.
    Reina-Campos, M., Moscat, J., and Diaz-Meco, M. (2017) Metabolism shapes the tumor microenvironment, Curr. Opin. Cell Biol., 48, 47–53, doi: Scholar
  40. 40.
    Bhome, R., Al Saihati, H. A., Goh, R. W., Bullock, M. D., Primrose, J. N., Thomas, G. J., Sayan, A. E., and Mirnezami, A. H. (2016) Translational aspects in targeting the stromal tumour microenvironment: from bench to bedside, New Horiz. Transl. Med., 3, 9–21, doi: Scholar
  41. 41.
    Bhome, R., Bullock, M. D., Al Saihati, H. A., Goh, R. W., Primrose, J. N., Sayan, A. E., and Mirnezami, A. H. (2015) A top-down view of the tumor microenvironment: structure, cells and signaling, Front. Cell Dev. Biol., 3, 33, doi: Scholar
  42. 42.
    Bhome, R., Mellone, M., Emo, K., Thomas, G. J., Sayan, A. E., and Mirnezami, A. H. (2018) The colorectal cancer microenvironment: strategies for studying the role of cancer-associated fibroblasts, Methods Mol. Biol., 1765, 87–98, doi: Scholar
  43. 43.
    Kalluri, R. (2016) The biology and function of fibroblasts in cancer, Nat. Rev. Cancer, 16, 582–598, doi: Scholar
  44. 44.
    Kalluri, R., and Zeisberg, M. (2006) Fibroblasts in cancer, Nat. Rev. Cancer, 6, 392–401, doi: Scholar
  45. 45.
    LeBleu, V. S., and Kalluri, R. (2018) A peek into cancer-associated fibroblasts: origins, functions and translational impact, Dis. Model. Mech., 11, dmm029447, doi: Scholar
  46. 46.
    Valkenburg, K. C., de Groot, A. E., and Pienta, K. J. (2018) Targeting the tumour stroma to improve cancer therapy, Nat. Rev. Clin. Oncol., 15, 366–381, doi: Scholar
  47. 47.
    Sverdlov, E. D. (2016) Multidimensional complexity of cancer. Simple solutions are needed, Biochemistry (Moscow), 81, 731–738, doi: Scholar
  48. 48.
    Ramamonjisoa, N., and Ackerstaff, E. (2017) Characterization of the tumor microenvironment and tumor–stroma interaction by non-invasive preclinical imaging, Front. Oncol., 7, 3, doi: Scholar
  49. 49.
    Melzer, C., von der Ohe, J., and Hass, R. (2018) Concise review: crosstalk of mesenchymal stroma/stem-like cells with cancer cells provides therapeutic potential, Stem Cells, 36, 951–968, doi: Scholar
  50. 50.
    Lou, E., Zhai, E., Sarkari, A., Desir, S., Wong, P., Iizuka, Y., Yang, J., Subramanian, S., McCarthy, J., Bazzaro, M., and Steer, C. J. (2018) Cellular and molecular networking within the ecosystem of cancer cell communication via tunneling nanotubes, Front. Cell Dev. Biol., 6, 95, doi: Scholar
  51. 51.
    Wu, J. S., Sheng, S. R., Liang, X. H., and Tang, Y. L. (2017) The role of tumor microenvironment in collective tumor cell invasion, Future Oncol., 13, 991–1002, doi: Scholar
  52. 52.
    Chen, F., Zhuang, X., Lin, L., Yu, P., Wang, Y., Shi, Y., Hu, G., and Sun, Y. (2015) New horizons in tumor microenvi- ronment biology: challenges and opportunities, BMC Med., 13, 45, doi: Scholar
  53. 53.
    Gandellini, P., Andriani, F., Merlino, G., D’Aiuto, F., Roz, L., and Callari, M. (2015) 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., 35, 96–106, doi: Scholar
  54. 54.
    Stadler, M., Walter, S., Walzl, A., Kramer, N., Unger, C., Scherzer, M., Unterleuthner, D., Hengstschlager, M., Krupitza, G., and Dolznig, H. (2015) Increased complexity in carcinomas: analyzing and modeling the interaction of human cancer cells with their microenvironment, Semin. Cancer Biol., 35, 107–124, doi: Scholar
  55. 55.
    Zi, F., He, J., He, D., Li, Y., Yang, L., and Cai, Z. (2015) Fibroblast activation protein alpha in tumor microenvironment: recent progression and implications (review), Mol. Med. Rep., 11, 3203–3211, doi: Scholar
  56. 56.
    Raffaghello, L., and Dazzi, F. (2015) Classification and biology of tumour associated stromal cells, Immunol. Lett., 168, 175–182, doi: Scholar
  57. 57.
    Sverdlov, E. (2018) Missed druggable cancer hallmark: cancer–stroma symbiotic crosstalk as paradigm and hypothesis for cancer therapy, Bioessays, 40, e1800079, doi: Scholar
  58. 58.
    Perrimon, N., Pitsouli, C., and Shilo, B. Z. (2012) Signaling mechanisms controlling cell fate and embryonic patterning, Cold Spring Harb. Perspect. Biol., 4, a005975, doi: Scholar
  59. 59.
    Bizzarri, M., and Cucina, A. (2014) Tumor and the microenvironment: a chance to reframe the paradigm of carcinogenesis? Biomed. Res. Int., 2014, 934038, doi: Scholar
  60. 60.
    Guo, F., Wang, Y., Liu, J., Mok, S. C., Xue, F., and Zhang, W. (2016) CXCL12/CXCR4: a symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks, Oncogene, 35, 816–826, doi: Scholar
  61. 61.
    Takakura, N. (2012) Formation and regulation of the cancer stem cell niche, Cancer Sci., 103, 1177–1181, doi: Scholar
  62. 62.
    Kise, K., Kinugasa-Katayama, Y., and Takakura, N. (2016) Tumor microenvironment for cancer stem cells, Adv. Drug Deliv. Rev., 99, 197–205, doi: Scholar
  63. 63.
    Park, T. S., Donnenberg, V. S., Donnenberg, A. D., Zambidis, E. T., and Zimmerlin, L. (2014) Dynamic interactions between cancer stem cells and their stromal partners, Curr. Pathobiol. Rep., 2, 41–52, doi: Scholar
  64. 64.
    Alvarez-Teijeiro, S., Garcia-Inclan, C., Villaronga, M. A., Casado, P., Hermida-Prado, F., Granda-Diaz, R., Rodrigo, J. P., Calvo, F., Del-Rio-Ibisate, N., Gandarillas, A., Moris, F., Hermsen, M., Cutillas, P., and Garcia-Pedrero, J. M. (2018) Factors secreted by cancer-associated fibroblasts that sustain cancer stem properties in head and neck squamous carcinoma cells as potential therapeutic targets, Cancers (Basel), 10, E334, doi: Scholar
  65. 65.
    Xiong, S., Wang, R., Chen, Q., Luo, J., Wang, J., Zhao, Z., Li, Y., Wang, Y., Wang, X., and Cheng, B. (2018) Cancer-associated fibroblasts promote stem cell-like properties of hepatocellular carcinoma cells through IL-6/STAT3/Notch signaling, Am. J. Cancer Res., 8, 302–316.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Ghiabi, P., Jiang, J., Pasquier, J., Maleki, M., Abu-Kaoud, N., Rafii, S., and Rafii, A. (2014) Endothelial cells provide a notch-dependent pro-tumoral niche for enhancing breast cancer survival, stemness and pro-metastatic properties, PLoS One, 9, e112424, doi: Scholar
  67. 67.
    Saltarella, I., Lamanuzzi, A., Reale, A., Vacca, A., and Ria, R. (2015) Identify multiple myeloma stem cells: utopia? World J. Stem Cells, 7, 84–95, doi: Scholar
  68. 68.
    Weiland, A., Roswall, P., Hatzihristidis, T. C., Pietras, K., Ostman, A., and Strell, C. (2012) Fibroblast-dependent regulation of the stem cell properties of cancer cells, Neoplasma, 59, 719–727, doi: Scholar
  69. 69.
    Xie, J., Tato, C. M., and Davis, M. M. (2013) How the immune system talks to itself: the varied role of synapses, Immunol. Rev., 251, 65–79, doi: Scholar
  70. 70.
    Terry, S., Savagner, P., Ortiz-Cuaran, S., Mahjoubi, L., Saintigny, P., Thiery, J. P., and Chouaib, S. (2017) New insights into the role of EMT in tumor immune escape, Mol. Oncol., 11, 824–846, doi: Scholar
  71. 71.
    Santi, A., Kugeratski, F. G., and Zanivan, S. (2018) Cancer associated fibroblasts: the architects of stroma remodeling, Proteomics, 18, e1700167, doi: Scholar
  72. 72.
    Marsh, T., Pietras, K., and McAllister, S. S. (2013) Fibroblasts as architects of cancer pathogenesis, Biochim. Biophys. Acta, 1832, 1070–1078, doi: Scholar
  73. 73.
    Liao, Z., Tan, Z. W., Zhu, P., and Tan, N. S. (2018) Cancer-associated fibroblasts in tumor microenvironment – accomplices in tumor malignancy, Cell. Immunol., pii: S0008-8749(17)30222-8, doi: [Epub ahead of print].
  74. 74.
    Ziani, L., Chouaib, S., and Thiery, J. (2018) Alteration of the antitumor immune response by cancer-associated fibroblasts, Front. Immunol., 9, 414, doi: Scholar
  75. 75.
    De Wever, O., Van Bockstal, M., Mareel, M., Hendrix, A., and Bracke, M. (2014) Carcinoma-associated fibroblasts provide operational flexibility in metastasis, Semin. Cancer Biol., 25, 33–46, doi: Scholar
  76. 76.
    Heneberg, P. (2016) Paracrine tumor signaling induces transdifferentiation of surrounding fibroblasts, Crit. Rev. Oncol. Hematol., 97, 303–311, doi: Scholar
  77. 77.
    Augsten, M. (2014) Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment, Front. Oncol., 4, 62, doi: Scholar
  78. 78.
    Tao, L., Huang, G., Song, H., Chen, Y., and Chen, L. (2017) Cancer associated fibroblasts: an essential role in the tumor microenvironment, Oncol. Lett., 14, 2611–2620, doi: Scholar
  79. 79.
    Bu, L., Baba, H., Yoshida, N., Miyake, K., Yasuda, T., Uchihara, T., Tan, P., and Ishimoto, T. (2019) Biological heterogeneity and versatility of cancer-associated fibroblasts in the tumor microenvironment, Oncogene, doi:
  80. 80.
    Du, H., and Che, G. (2017) Genetic alterations and epigenetic alterations of cancer-associated fibroblasts, Oncol. Lett., 13, 3–12, doi: Scholar
  81. 81.
    Belli, C., Trapani, D., Viale, G., D’Amico, P., Duso, B. A., Della Vigna, P., Orsi, F., and Curigliano, G. (2018) Targeting the microenvironment in solid tumors, Cancer Treat. Rev., 65, 22–32, doi: Scholar
  82. 82.
    Gaggioli, C., Hooper, S., Hidalgo-Carcedo, C., Grosse, R., Marshall, J. F., Harrington, K., and Sahai, E. (2007) Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells, Nat. Cell Biol., 9, 1392–1400, doi: Scholar
  83. 83.
    Semba, S., Kodama, Y., Ohnuma, K., Mizuuchi, E., Masuda, R., Yashiro, M., Hirakawa, K., and Yokozaki, H. (2009) Direct cancer–stromal interaction increases fibroblast proliferation and enhances invasive properties of scirrhous-type gastric carcinoma cells, Br. J. Cancer, 101, 1365–1373, doi: Scholar
  84. 84.
    Choe, C., Shin, Y. S., Kim, S. H., Jeon, M. J., Choi, S. J., Lee, J., and Kim, J. (2013) Tumor–stromal interactions with direct cell contacts enhance motility of non-small cell lung cancer cells through the hedgehog signaling pathway, Anticancer Res., 33, 3715–3723.PubMedGoogle Scholar
  85. 85.
    He, X. J., Tao, H. Q., Hu, Z. M., Ma, Y. Y., Xu, J., Wang, H. J., Xia, Y. J., Li, L., Fei, B. Y., Li, Y. Q., and Chen, J. Z. (2014) Expression of galectin-1 in carcinoma-associated fibroblasts promotes gastric cancer cell invasion through upregulation of integrin beta1, Cancer Sci., 105, 1402–1410, doi: Scholar
  86. 86.
    Yamaguchi, H., and Sakai, R. (2015) Direct interaction between carcinoma cells and cancer associated fibroblasts for the regulation of cancer invasion, Cancers (Basel), 7, 2054–2062, doi: Scholar
  87. 87.
    Labernadie, A., Kato, T., Brugues, A., Serra-Picamal, X., Derzsi, S., Arwert, E., Weston, A., Gonzalez-Tarrago, V., Elosegui-Artola, A., Albertazzi, L., Alcaraz, J., Roca-Cusachs, P., Sahai, E., and Trepat, X. (2017) A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion, Nat. Cell Biol., 19, 224–237, doi: Scholar
  88. 88.
    Theveneau, E., and Linker, C. (2017) Leaders in collective migration: are front cells really endowed with a particular set of skills? F1000Res, 6, 1899, doi: Scholar
  89. 89.
    Wang, B. (2011) Cancer cells exploit the Eph–ephrin system to promote invasion and metastasis: tales of unwitting partners, Sci. Signaling, 4, pe28, doi: Scholar
  90. 90.
    Attieh, Y., Clark, A. G., Grass, C., Richon, S., Pocard, M., Mariani, P., Elkhatib, N., Betz, T., Gurchenkov, B., and Vignjevic, D. M. (2017) Cancer-associated fibroblasts lead tumor invasion through integrin-beta3-dependent fibronectin assembly, J. Cell Biol., 216, 3509–3520, doi: Scholar
  91. 91.
    Le Bras, S., and Le Borgne, R. (2014) Epithelial cell division – multiplying without losing touch, J. Cell Sci., 127, 5127–5137, doi: Scholar
  92. 92.
    Karagiannis, G. S., Poutahidis, T., Erdman, S. E., Kirsch, R., Riddell, R. H., and Diamandis, E. P. (2012) Cancer-associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue, Mol. Cancer Res., 10, 1403–1418, doi: Scholar
  93. 93.
    Cohen, D. J., and Nelson, W. J. (2018) Secret handshakes: cell–cell interactions and cellular mimics, Curr. Opin. Cell Biol., 50, 14–19, doi: Scholar
  94. 94.
    Serge, A. (2016) The molecular architecture of cell adhesion: dynamic remodeling revealed by videonanoscopy, Front. Cell Dev. Biol., 4, 36, doi: Scholar
  95. 95.
    Price, A. J., Cost, A. L., Ungewiss, H., Waschke, J., Dunn, A. R., and Grashoff, C. (2018) Mechanical loading of desmosomes depends on the magnitude and orientation of external stress, Nat. Commun., 9, 5284, doi: Scholar
  96. 96.
    Sahu, P., Jena, S. R., and Samanta, L. (2018) Tunneling nanotubes: a versatile target for cancer therapy, Curr. Cancer Drug Targets, 18, 514–521, doi: Scholar
  97. 97.
    Jacquemet, G., Hamidi, H., and Ivaska, J. (2015) Filopodia in cell adhesion, 3D migration and cancer cell invasion, Curr. Opin. Cell Biol., 36, 23–31, doi: Scholar
  98. 98.
    Kornberg, T. B. (2017) Distributing signaling proteins in space and time: the province of cytonemes, Curr. Opin. Genet. Dev., 45, 22–27, doi: Scholar
  99. 99.
    Mattes, B., and Scholpp, S. (2018) Emerging role of contact-mediated cell communication in tissue development and diseases, Histochem. Cell Biol., 150, 431–442, doi: Scholar
  100. 100.
    Fairchild, C. L., and Barna, M. (2014) Specialized filopodia: at the “tip” of morphogen transport and vertebrate tissue patterning, Curr. Opin. Genet. Dev., 27, 67–73, doi: Scholar
  101. 101.
    Caviglia, S., and Ober, E. A. (2018) Non-conventional protrusions: the diversity of cell interactions at short and long distance, Curr. Opin. Cell Biol., 54, 106–113, doi: Scholar
  102. 102.
    Humphries, J. D., Paul, N. R., Humphries, M. J., and Morgan, M. R. (2015) Emerging properties of adhesion complexes: what are they and what do they do? Trends Cell Biol., 25, 388–397, doi: Scholar
  103. 103.
    Su, S., Chen, J., Yao, H., Liu, J., Yu, S., Lao, L., Wang, M., Luo, M., Xing, Y., Chen, F., Huang, D., Zhao, J., Yang, L., Liao, D., Su, F., Li, M., Liu, Q., and Song, E. (2018) CD10(+)GPR77(+) cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness, Cell, 172, 841–856.e16, doi: Scholar
  104. 104.
    Kaiser, J. (2015) The cancer stem cell gamble, Science, 347, 226–229, doi: Scholar
  105. 105.
    Kuhlmann, L., Cummins, E., Samudio, I., and Kislinger, T. (2018) Cell-surface proteomics for the identification of novel therapeutic targets in cancer, Expert Rev. Proteomics, 15, 259–275, doi: Scholar
  106. 106.
    Kim, J. W., and Cochran, J. R. (2017) Targeting ligand–receptor interactions for development of cancer therapeutics, Curr. Opin. Chem. Biol., 38, 62–69, doi: Scholar
  107. 107.
    Weikl, T., Asfaw, M., Krobath, H., Rozycki, B., and Lipowsky, R. (2009) Adhesion of membranes via receptor–ligand complexes: domain formation, binding cooper-ativity, and active processes, Soft Matter, 5, 3213–3224, doi: Scholar
  108. 108.
    Cogdill, A. P., Andrews, M. C., and Wargo, J. A. (2017) Hallmarks of response to immune checkpoint blockade, Br. J. Cancer, 117, 1–7, doi: Scholar

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© Pleiades Publishing, Ltd. 2019

Authors and Affiliations

  1. 1.Institute of Molecular GeneticsRussian Academy of SciencesMoscowRussia
  2. 2.Shemyakin-Ovchinnikov Institute of Bioorganic ChemistryRussian Academy of SciencesMoscowRussia

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