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Hallmarks of an Aging and Malignant Tumor Microenvironment and the Rise of Resilient Cell Subpopulations

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Engineering and Physical Approaches to Cancer

Part of the book series: Current Cancer Research ((CUCR))

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Abstract

Intratumor heterogeneity, which includes intrinsic differences in cancer cells and morphological differences in the tissue architectures, represents a major challenge in understanding and treating cancer. Additionally, physical and molecular interactions between cancer cells and their surrounding tumor microenvironment, with its diversity in cell types and matrix mechanics, play a critical role in directing tumor growth and cancer progression. This chapter discusses how physical and molecular aspects of hallmark cancer traits and the tumor microenvironment have contributed to our understanding of cancer cell behavior. We discuss how the evolution of a malignant tumor microenvironment can protect, foster, and even prime stromal and cancer populations against future therapy-associated stress. Specifically, we highlight the development of senescent stromal populations and polyploidal giant cancer cells – resilient subpopulations contributing to chemoresistance and disease recurrence. We summarize key studies used to profile cell forces, cytoskeletal mechanics, and a number of other cell variables (i.e., morphology, migration, proliferation) that are important in cancer progression. These physical approaches are combined with molecular analysis to systematically examine tumor microenvironment conditions that control cell behavior, prime against therapeutic interventions, and contribute to the inherent heterogeneity in tumor microenvironments.

Authors Carolina Mejia Peña and Amy H. Lee have equally contributed to this chapter.

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References

  1. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  CAS  PubMed  Google Scholar 

  2. Hanahan D et al (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  3. Hanahan D (2022) Hallmarks of cancer: new dimensions. Cancer Discov 12:31–46

    Article  CAS  PubMed  Google Scholar 

  4. Mierke CT (2013) Physical break-down of the classical view on cancer cell invasion and metastasis. Eur J Cell Biol 92:89–104

    Article  CAS  PubMed  Google Scholar 

  5. Pickup MW, Mouw JK, Weaver VM (2014) The extracellular matrix modulates the hallmarks of cancer. EMBO Rep 15

    Google Scholar 

  6. Nia HT et al (2016) Solid stress and elastic energy as measures of tumour mechanopathology. Nat Biomed Eng 1

    Google Scholar 

  7. Xu W et al (2012) Cell stiffness is a biomarker of the metastatic potential of ovarian cancer cells. PLoS One 7:e46609–e46609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Butcher DT, Alliston T, Weaver VM (2009) A tense situation: forcing tumour progression. Nat Rev Cancer 9:108–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mierke CT (2013) Invasive cancer cells and metastasis. Phys Biol 10:60301

    Article  Google Scholar 

  10. Paszek MJ et al (2005) Tensional homeostasis and the malignant phenotype. Cancer Cell 8:241–254

    Article  CAS  PubMed  Google Scholar 

  11. Joyce JA, Pollard JW (2009) Microenvironmental regulation of metastasis. Nat Rev Cancer 9:239–252

    Article  CAS  PubMed  Google Scholar 

  12. Stanta G, Bonin S (2018) Overview on clinical relevance of intra-tumor heterogeneity. Front Med 5. Preprint at https://doi.org/10.3389/fmed.2018.00085

  13. Fidler IJ (1978) Tumor heterogeneity and the biology of cancer invasion and metastasis. Cancer Res 38:2651–2660

    CAS  PubMed  Google Scholar 

  14. Kaplan RN, Rafii S, Lyden D (2006) Preparing the “soil”: the premetastatic niche. Cancer Res 66:11089–11093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Quail DF, Joyce JA (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med 19:11 19, 1423–1437

    Google Scholar 

  16. Morales-Valencia J, David G (2021) The contribution of physiological and accelerated aging to cancer progression through senescence-induced inflammation. Front Oncol 11:747822

    Article  PubMed  PubMed Central  Google Scholar 

  17. Campisi J (2013) Aging, cellular senescence, and cancer. Annu Rev Physiol 75:685–705

    Article  CAS  PubMed  Google Scholar 

  18. Ghosh D et al (2020) Senescent mesenchymal stem cells remodel extracellular matrix driving breast cancer cells to a more-invasive phenotype. J Cell Sci 133:jcs232470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ganem NJ, Storchova Z, Pellman D (2007) Tetraploidy, aneuploidy and cancer. Curr Opin Genet Dev 17:157–162

    Article  CAS  PubMed  Google Scholar 

  20. Xuan B, Ghosh D, Cheney EM, Clifton EM, Dawson MR (2018) Dysregulation in actin cytoskeletal organization drives increased stiffness and migratory persistence in polyploidal giant cancer cells. Sci Rep 8:11935

    Article  PubMed  PubMed Central  Google Scholar 

  21. Xuan B, Ghosh D, Dawson MR (2022) Contributions of the distinct biophysical phenotype of polyploidal giant cancer cells to cancer progression. Semin Cancer Biol 81:64–72

    Article  CAS  PubMed  Google Scholar 

  22. Arneth B (2020) Tumor microenvironment. Medicina 56

    Google Scholar 

  23. Mcmillin DW, Negri JM, Mitsiades CS (2013) The role of tumour-stromal interactions in modifying drug response: challenges and opportunities. Nat Rev Drug Discov 12:217–228

    Article  CAS  PubMed  Google Scholar 

  24. Dawson MR, Duda DG, Chae S-SS, Fukumura D, Jain RK (2009) VEGFR1 activity modulates myeloid cell infiltration in growing lung metastases but is not required for spontaneous metastasis formation. PLoS One 4:e6525

    Article  PubMed  PubMed Central  Google Scholar 

  25. Jain RK (2013) Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol 31. Preprint at https://doi.org/10.1200/JCO.2012.46.3653

  26. Psaila B, Lyden D (2009) The metastatic niche: adapting the foreign soil. Nat Rev Cancer 9:285–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Langley RR, Fidler IJ (2011) The seed and soil hypothesis revisited—the role of tumor-stroma interactions in metastasis to different organs. Int J Cancer 128:2527–2535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wirtz D (2009) Particle-tracking microrheology of living cells: principles and applications. Annu Rev Biophys 38:301–326

    Article  CAS  PubMed  Google Scholar 

  29. Hart IR, Fidler IJ (1980) Role of organ selectivity in the determination of metastatic patterns of B16 melanoma. Cancer Res 40:2281–2287

    CAS  PubMed  Google Scholar 

  30. Whiteside TL (2008) The tumor microenvironment and its role in promoting tumor growth. Oncogene 27:5904–5912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Franklin RA et al (2014) The cellular and molecular origin of tumor-associated macrophages. Science 344:921–925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lindau D, Gielen P, Kroesen M, Wesseling P, Adema GJ (2013) The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells. Immunology 138:105–115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bos PD, Plitas G, Rudra D, Lee SY, Rudensky AY (2013) Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy. J Exp Med 210:2435–2466

    Article  PubMed  PubMed Central  Google Scholar 

  34. Barry KC et al (2018) A natural killer–dendritic cell axis defines checkpoint therapy–responsive tumor microenvironments. Nat Med 24:1178–1191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shiao SL, Preethi Ganesan A, Rugo HS, Coussens LM (2011) Immune microenvironments in solid tumors: new targets for therapy. Genes Dev 25:2559–2572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Balkwill FR, Capasso M, Hagemann T (2012) The tumor microenvironment at a glance. J Cell Sci 125:5591–5596

    Article  CAS  PubMed  Google Scholar 

  37. Corn KC, Windham MA, Rafat M (2020) Lipids in the tumor microenvironment: from cancer progression to treatment. Prog Lipid Res 80:101055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kojima Y et al (2010) Autocrine TGF-β and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc Natl Acad Sci USA 107:20009–20014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Luo H, Tu G, Liu Z, Liu M (2015) Cancer-associated fibroblasts: a multifaceted driver of breast cancer progression. Cancer Lett 361:155–163. Preprint at https://doi.org/10.1016/j.canlet.2015.02.018

  40. Truffi M, Sorrentino L, Corsi F (2020) Fibroblasts in the tumor microenvironment. Undefined 1234:15–29

    CAS  Google Scholar 

  41. Kidd S et al (2012) Origins of the tumor microenvironment: quantitative assessment of adipose-derived and bone marrow-derived stroma. PLoS One 7:e30563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ferrara N, Kerbel RS (2005) Angiogenesis as a therapeutic target. Nature 438:967–974

    Article  CAS  PubMed  Google Scholar 

  43. McGrail DJ, McAndrews KM, Dawson MR (2013) Biomechanical analysis predicts decreased human mesenchymal stem cell function before molecular differences. Exp Cell Res 319:684–696

    Article  CAS  PubMed  Google Scholar 

  44. McGrail DJ, Ghosh D, Quach ND, Dawson MR (2012) Differential mechanical response of mesenchymal stem cells and fibroblasts to tumor-secreted soluble factors. PLoS One 7:e33248. https://doi.org/10.1371/journal.pone.0033248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hass R, Kasper C, Böhm S, Jacobs R (2011) Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal 9:12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Erez N et al (2010) Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell 17:135–147

    Article  CAS  PubMed  Google Scholar 

  47. Xiao Y et al (2019) Multi-omics profiling reveals distinct microenvironment characterization and suggests immune escape mechanisms of triple-negative breast cancer. Clin Cancer Res 25:5002–5014

    Article  CAS  PubMed  Google Scholar 

  48. Duan Q, Zhang H, Zheng J, Zhang L (2020) Turning cold into hot: firing up the tumor microenvironment. Trends Cancer 6:605–618

    Article  CAS  PubMed  Google Scholar 

  49. Bonaventura P et al (2019) Cold Tumors: a therapeutic challenge for immunotherapy. Front Immunol 10:168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Grinnell F (2003) Fibroblast biology in three-dimensional collagen matrices. Trends Cell Biol 13:264–269

    Article  CAS  PubMed  Google Scholar 

  51. Tamariz E, Grinnell F (2002) Modulation of fibroblast morphology and adhesion during collagen matrix remodeling. Mol Biol Cell 13:3915–3929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Levental KR et al (2009) Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139:891–906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401

    Article  CAS  PubMed  Google Scholar 

  54. Räsänen K, Vaheri A (2010) Activation of fibroblasts in cancer stroma. Exp Cell Res 316:2713–2722. Academic Press

    Google Scholar 

  55. Carey SP, Martin KE, Reinhart-King CA (2017) Three-dimensional collagen matrix induces a mechanosensitive invasive epithelial phenotype. Sci Rep 7

    Google Scholar 

  56. Calvo F et al (2013) Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat Cell Biol 15:637–646

    Article  CAS  PubMed  Google Scholar 

  57. Costa A et al (2018) Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer. Cancer Cell 33:463–479.e10

    Google Scholar 

  58. Barrett R, Puré E (2020) Cancer-associated fibroblasts: key determinants of tumor immunity and immunotherapy. Curr Opin Immunol 64:80–87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wolf K, Friedl P (2011) Extracellular matrix determinants of proteolytic and non-proteolytic cell migration. Trends Cell Biol 21:736–744. Preprint at https://doi.org/10.1016/j.tcb.2011.09.006

  60. Egeblad M, Rasch MG, Weaver VM (2010) Dynamic interplay between the collagen scaffold and tumor evolution. Curr Opin Cell Biol 22:697–706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wolf K et al (2007) Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion. Nat Cell Biol 9:893–904

    Article  CAS  PubMed  Google Scholar 

  62. Oskarsson T (2013) Extracellular matrix components in breast cancer progression and metastasis. Breast 22(Suppl 2):S66–S72

    Article  PubMed  Google Scholar 

  63. Acerbi I et al (2015) Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr Biol 7:1120–1134

    Article  CAS  Google Scholar 

  64. Thiery JP, Acloque H, Huang RYJ, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890

    Article  CAS  PubMed  Google Scholar 

  65. Lu P, Weaver VM, Werb Z (2012) The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol 196:395–406. Preprint at https://doi.org/10.1083/jcb.201102147

  66. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186

    Article  CAS  PubMed  Google Scholar 

  67. Humar R, Kiefer FN, Berns H, Resink TJ, Battegay EJ (2002) Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling. The FASEB J 16:771–780

    Article  CAS  PubMed  Google Scholar 

  68. Carmeliet P (2005) VEGF as a key mediator of angiogenesis in cancer. Oncology 69:4–10. Preprint at https://doi.org/10.1159/000088478

  69. Holmgren L, O’Reilly MS, Folkman J (1995) Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1:149–153

    Article  CAS  PubMed  Google Scholar 

  70. Folkman J (2006) Angiogenesis. Annu Rev Med 57:1–18

    Article  CAS  PubMed  Google Scholar 

  71. Ferrara N, Hillan KJ, Gerber H-P, Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3:391–400

    Article  CAS  PubMed  Google Scholar 

  72. Goel S, Wong AH-K, Jain RK (2012) Vascular normalization as a therapeutic strategy for malignant and nonmalignant disease. Cold Spring Harb Perspect Med 2:a006486–a006486

    Article  PubMed  PubMed Central  Google Scholar 

  73. Vasudev NS, Reynolds AR (2014) Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. Angiogenesis 17:471–494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Chauhan VP et al (2012) Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nat Nanotechnol 7:383–388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Peinado H, Lavotshkin S, Lyden D (2011) The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin Cancer Biol 21:139–146

    Article  CAS  PubMed  Google Scholar 

  76. Fridman AL, Tainsky MA (2008) Critical pathways in cellular senescence and immortalization revealed by gene expression profiling. Oncogene 27:5975–5987

    Article  CAS  PubMed  Google Scholar 

  77. Semenza GL (2009) Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin Cancer Biol 19:12–16

    Article  CAS  PubMed  Google Scholar 

  78. Semenza G, Targeting L (2003) HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732

    Article  CAS  PubMed  Google Scholar 

  79. Palmieri D et al (2007) Her-2 overexpression increases the metastatic outgrowth of breast cancer cells in the brain. Cancer Res 67:4190–4198

    Article  CAS  PubMed  Google Scholar 

  80. Yap TA, Carden CP, Kaye SB (2009) Beyond chemotherapy: targeted therapies in ovarian cancer. Nat Rev Cancer 9:167–181

    Article  CAS  PubMed  Google Scholar 

  81. Chen F et al (2015) New horizons in tumor microenvironment biology: challenges and opportunities. BMC Med 13

    Google Scholar 

  82. Chow LQM, Eckhardt SG (2007) Sunitinib: from rational design to clinical efficacy. J Clin Oncol 25:884–896

    Article  CAS  PubMed  Google Scholar 

  83. Shah NP et al (2004) Overriding imatinib resistance with a novel ABL kinase inhibitor. Science (New York, N.Y.) 305:399–401

    Article  CAS  PubMed  Google Scholar 

  84. Matei D et al (2008) Imatinib mesylate in combination with docetaxel for the treatment of patients with advanced, platinum-resistant ovarian cancer and primary peritoneal carcinomatosis : a Hoosier Oncology Group trial. Cancer 113:723–732

    Article  CAS  PubMed  Google Scholar 

  85. Melisi D et al (2008) LY2109761, a novel transforming growth factor receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Cancer Ther 7:829–840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Takai K et al (2016) Targeting the cancer-associated fibroblasts as a treatment in triple-negative breast cancer. Oncotarget 7:82889–82901

    Article  PubMed  PubMed Central  Google Scholar 

  87. Kalluri R (2016) The biology and function of exosomes in cancer 126:1208–1215

    Google Scholar 

  88. Hoshino A et al (2015) Tumour exosome integrins determine organotropic metastasis. Nature 527:329–335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Doyle LM, Wang MZ (2019) Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cell 8:727

    Article  CAS  Google Scholar 

  90. Lee AH, Ghosh D, Quach N, Schroeder D, Dawson MR (2020) Ovarian cancer exosomes trigger differential biophysical response in tumor-derived fibroblasts. Sci Rep 10:8686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Costa-Silva B et al (2015) Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol 17:816–826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Le MTN et al (2014) miR-200–containing extracellular vesicles promote breast cancer cell metastasis. J Clin Investig 124:5109–5128

    Article  PubMed  PubMed Central  Google Scholar 

  93. Logozzi M, Spugnini E, Mizzoni D, Di Raimo R, Fais S (2019) Extracellular acidity and increased exosome release as key phenotypes of malignant tumors. Cancer Metastasis Rev 38:93–101

    Article  CAS  PubMed  Google Scholar 

  94. Chen X et al (2017) Exosomes derived from hypoxic epithelial ovarian cancer deliver microRNA-940 to induce macrophage M2 polarization. Oncol Rep 38:522–528

    Article  CAS  PubMed  Google Scholar 

  95. Han L, Lam EW-F, Sun Y. Extracellular vesicles in the tumor microenvironment: old stories, but new tales. https://doi.org/10.1186/s12943-019-0980-8

  96. McGranahan N, Swanton C (2015) Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell 27:15–26

    Article  CAS  PubMed  Google Scholar 

  97. Kreso A et al (2013) Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science (New York, N.Y.) 339:543–548

    Article  CAS  PubMed  Google Scholar 

  98. Wu P-H et al (2015) Evolution of cellular morpho-phenotypes in cancer metastasis. Sci Rep 5:18437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Lee AH, Mejia Peña C, Dawson MR (2022) Comparing the secretomes of chemorefractory and chemoresistant ovarian cancer cell populations. Cancers 14:1418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Zhang K et al (2022) Longitudinal single-cell RNA-seq analysis reveals stress-promoted chemoresistance in metastatic ovarian cancer. Sci Adv 8:eabm1831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Jain RK, Martin JD, Stylianopoulos T (2014) The role of mechanical forces in tumor growth and therapy. Annu Rev Biomed Eng 16:321–346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Northcott JM, Dean IS, Mouw JK, Weaver VM (2018) Feeling stress: the mechanics of cancer progression and aggression. Front Cell Dev Biol 6:17

    Article  PubMed  PubMed Central  Google Scholar 

  103. Mitchell M, King M (2013) Computational and experimental models of cancer cell response to fluid shear stress. Front Oncol 3

    Google Scholar 

  104. Rice AJ et al (2017) Matrix stiffness induces epithelial–mesenchymal transition and promotes chemoresistance in pancreatic cancer cells. Oncogenesis 6:e352–e352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Novak C, Horst E, Mehta G (2018) Review: Mechanotransduction in ovarian cancer: shearing into the unknown. APL Bioeng 2:031701

    Article  PubMed  PubMed Central  Google Scholar 

  106. Bregenzer ME et al (2019) The role of cancer stem cells and mechanical forces in ovarian cancer metastasis. Cancers (Basel) 11:1008

    Article  CAS  PubMed  Google Scholar 

  107. Chiang SPH, Cabrera RM, Segall JE (2016) Tumor cell intravasation. Am J Physiol Cell Physiol 311:C1–C14

    Article  PubMed  PubMed Central  Google Scholar 

  108. Yankaskas CL et al (2021) The fluid shear stress sensor TRPM7 regulates tumor cell intravasation. Sci Adv 7:eabh3457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Erenpreisa J, Cragg MS (2013) Three steps to the immortality of cancer cells: senescence, polyploidy and self-renewal. Cancer Cell Int 13:92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Saleh T, Tyutyunyk-Massey L, Gewirtz DA (2019) Tumor cell escape from therapy-induced senescence as a model of disease recurrence after dormancy. Cancer Res 79:1044–1046

    Article  CAS  PubMed  Google Scholar 

  111. Ghosh D et al (2014) Integral role of platelet-derived growth factor in mediating transforming growth factor-β1-dependent mesenchymal stem cell stiffening. Stem Cells Dev 23:245–261

    Article  CAS  PubMed  Google Scholar 

  112. Kumar S, Weaver VM (2009) Mechanics, malignancy, and metastasis: the force journey of a tumor cell. Cancer Metastasis Rev 28:113–127

    Article  PubMed  PubMed Central  Google Scholar 

  113. Thomas TS et al (2020) Advancing age and the risk of bleomycin pulmonary toxicity in a largely older cohort of patients with newly diagnosed Hodgkin Lymphoma. J Geriatr Oncol 11:69–74

    Article  PubMed  Google Scholar 

  114. Pan J et al (2017) Inhibition of Bcl-2/xl with ABT-263 selectively kills senescent type II Pneumocytes and reverses persistent pulmonary fibrosis induced by ionizing radiation in mice. Int J Radiat Oncol *Biology* Physics 99:353–361

    Article  CAS  Google Scholar 

  115. Ewald JA, Desotelle JA, Wilding G, Jarrard DF (2010) Therapy-induced senescence in cancer. JNCI: J Nat Cancer Inst 102:1536–1546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Coppé J-P, Desprez P-Y, Krtolica A, Campisi J (2010) The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 5:99–118

    Article  PubMed  PubMed Central  Google Scholar 

  117. White-Gilbertson S, Voelkel-Johnson C (2020) Giants and monsters: unexpected characters in the story of cancer recurrence. Adv Cancer Res 148:201–232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Song Y, Zhao Y, Deng Z, Zhao R, Huang Q (2021) Stress-induced polyploid giant cancer cells: unique way of formation and non-negligible characteristics. Front Oncol 11:724781

    Article  PubMed  PubMed Central  Google Scholar 

  119. Murray D, Mirzayans R (2020) Cellular responses to platinum-based anticancer drugs and UVC: role of p53 and implications for cancer therapy. Int J Mol Sci 21

    Google Scholar 

  120. Wang Q et al (2013) Polyploidy road to therapy-induced cellular senescence and escape. Int J Cancer 132:1505–1515

    Article  CAS  PubMed  Google Scholar 

  121. Jin J et al (2019) Pirfenidone attenuates lung fibrotic fibroblast responses to transforming growth factor-β1. Respir Res 20:119

    Article  PubMed  PubMed Central  Google Scholar 

  122. Shi Y, Massague J (2003) Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113:685–700

    Article  CAS  PubMed  Google Scholar 

  123. Ghosh D, McGrail DJDJ, Dawson MRMR (2017) TGF-β1 pretreatment improves the function of mesenchymal stem cells in the wound bed. Front Cell Dev Biol 5

    Google Scholar 

  124. McAndrews KM, McGrail DJ, Ravikumar N, Dawson MR (2015) Mesenchymal stem cells induce directional migration of invasive breast cancer cells through TGF-β. Sci Rep. https://doi.org/10.1038/srep16941

  125. He Y et al (2019) Cellular senescence and radiation-induced pulmonary fibrosis. Transl Res J Lab Clin Med 209:14–21

    Google Scholar 

  126. Justice JN et al (2019) Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine 40:554–563

    Article  PubMed  PubMed Central  Google Scholar 

  127. Li M, You L, Xue J, Lu Y (2018) Ionizing radiation-induced cellular senescence in normal, non-transformed cells and the involved DNA damage response: A mini review. Front Pharmacol. Preprint at https://doi.org/10.3389/fphar.2018.00522

  128. Kirkland JL, Tchkonia T (2015) Clinical strategies and animal models for developing senolytic agents. Exp Gerontol 68:19–25

    Article  CAS  PubMed  Google Scholar 

  129. Malavolta M et al (2018) Inducers of senescence, toxic compounds, and senolytics: the multiple faces of Nrf2-activating phytochemicals in cancer adjuvant therapy. Mediat Inflamm 2018:4159013

    Article  Google Scholar 

  130. Amend SR et al (2019) Polyploid giant cancer cells: unrecognized actuators of tumorigenesis, metastasis, and resistance. Prostate 79:1489–1497

    Article  PubMed  PubMed Central  Google Scholar 

  131. Zhang S, Zhang D, Yang Z, Zhang X (2016) Tumor budding, micropapillary pattern, and polyploidy Giant cancer cells in colorectal cancer: current status and future prospects. Stem Cells Int 2016:4810734

    Article  PubMed  PubMed Central  Google Scholar 

  132. Mirzayans, R., Andrais, B. & Murray, D. (2018) Roles of polyploid/multinucleated giant cancer cells in metastasis and disease relapse following anticancer treatment. Cancers 10. Preprint at https://doi.org/10.3390/cancers10040118

  133. Cheng B, Crasta K (2017) Consequences of mitotic slippage for antimicrotubule drug therapy. Endocr Relat Cancer 24:T97–T106

    Article  CAS  PubMed  Google Scholar 

  134. Bastida-Ruiz D, Van Hoesen K, Cohen M (2016) The dark side of cell fusion. Int J Mol Sci 17:E638

    Article  Google Scholar 

  135. Pirsko V et al (2019) Alterations of the stem-like properties in the breast cancer cell line MDA-MB-231 induced by single pulsed doxorubicin treatment. Proceedings of the Latvian Academy of Sciences. Section B. Natural, Exact, and Applied Sciences 73:89–99

    Article  CAS  Google Scholar 

  136. Sasai K et al (2004) Aurora-C kinase is a novel chromosomal passenger protein that can complement Aurora-B kinase function in mitotic cells. Cell Motility and the Cytoskeleton 59:249–263

    Article  CAS  PubMed  Google Scholar 

  137. Niu N et al (2016) Linking genomic reorganization to tumor initiation via the giant cell cycle. Oncogenesis 5:e281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Niu N, Mercado-Uribe I, Liu J (2017) Dedifferentiation into blastomere-like cancer stem cells via formation of polyploid giant cancer cells. Oncogene 36:4887–4900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Zhang S et al (2014) Generation of cancer stem-like cells through the formation of polyploid giant cancer cells. Oncogene 33:116–128

    Article  CAS  PubMed  Google Scholar 

  140. Lopez-Sánchez LM et al (2014) CoCl2, a mimic of hypoxia, induces formation of polyploid giant cells with stem characteristics in colon cancer. PLoS One 9

    Google Scholar 

  141. Fei F et al (2015) The number of polyploid giant cancer cells and epithelial-mesenchymal transition-related proteins are associated with invasion and metastasis in human breast cancer. J Exp Clin Cancer Res 34:1–13

    Article  Google Scholar 

  142. Xuan B, Ghosh D, Jiang J, Shao R, Dawson MR (2020) Vimentin filaments drive migratory persistence in polyploidal cancer cells. Proc Natl Acad Sci USA 117

    Google Scholar 

  143. Mendez MG, Restle D, Janmey PA (2014) Vimentin enhances cell elastic behavior and protects against compressive stress. Biophys J 107:314–323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Hu J et al (2019) High stretchability, strength, and toughness of living cells enabled by hyperelastic vimentin intermediate filaments. Proc Natl Acad Sci 116:17175–17180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Peña, C.M., Lee, A.H., Frare, M.F., Ghosh, D., Dawson, M.R. (2023). Hallmarks of an Aging and Malignant Tumor Microenvironment and the Rise of Resilient Cell Subpopulations. In: Wong, I.Y., Dawson, M.R. (eds) Engineering and Physical Approaches to Cancer. Current Cancer Research. Springer, Cham. https://doi.org/10.1007/978-3-031-22802-5_4

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