Skip to main content

Advertisement

Log in

The functional multipotency of transforming growth factor β signaling at the intersection of senescence and cancer

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

The transforming growth factor β (TGF-β) family of cytokines comprises a group of proteins, their receptors, and effector molecules that, in a coordinated manner, modulate a plethora of physiological and pathophysiological processes. TGF-β1 is the best known and plausibly most active representative of this group. It acts as an immunosuppressant, contributes to extracellular matrix remodeling, and stimulates tissue fibrosis, differentiation, angiogenesis, and epithelial-mesenchymal transition. In recent years, this cytokine has been established as a vital regulator of organismal aging and cellular senescence. Finally, the role of TGF-β1 in cancer progression is no longer in question. Because this protein is involved in so many, often overlapping phenomena, the question arises whether it can be considered a molecular bridge linking some of these phenomena together and governing their reciprocal interactions. In this study, we reviewed the literature from the perspective of the role of various TGF-β family members as regulators of a complex mutual interplay between senescence and cancer. These aspects are then considered in a broader context of remaining TGF-β-related functions and coexisting processes. The main narrative axis in this work is centered around the interaction between the senescence of normal peritoneal cells and ovarian cancer cells. The discussion also includes examples of TGF-β activity at the interface of other normal and cancer cell types.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Availability of data and material

Not applicable.

References

  1. Dinarello CA (2007) Historical insights into cytokines. Eur J Immunol 37(Suppl 1):S34-45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Akdis M, Aab A, Altunbulakli C, Azkur K, Costa RA, Crameri R, Duan S, Eiwegger T, Eljaszewicz A, Ferstl R, Frei R, Garbani M, Globinska A, Hess L, Huitema C, Kubo T, Komlosi Z, Konieczna P, Kovacs N, Kucuksezer UC, Meyer N, Morita H, Olzhausen J, O’Mahony L, Pezer M, Prati M, Rebane A, Rhyner C, Rinaldi A, Sokolowska M, Stanic B, Sugita K, Treis A, van de Veen W, Wanke K, Wawrzyniak M, Wawrzyniak P, Wirz OF, Zakzuk JS, Akdis CA (2016) Interleukins (from IL-1 to IL-38), interferons, transforming growth factor beta, and TNF-alpha: receptors, functions, and roles in diseases. J Allergy Clin Immunol 138:984–1010

    Article  CAS  PubMed  Google Scholar 

  3. Turner MD, Nedjai B, Hurst T, Pennington DJ (2014) Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta 1843:2563–2582

    Article  CAS  PubMed  Google Scholar 

  4. Lan T, Chen L, Wei X (2021) Inflammatory cytokines in cancer: comprehensive understanding and clinical progress in gene therapy. Cells 10:100

    Article  CAS  PubMed Central  Google Scholar 

  5. Rea IM, Gibson DS, McGilligan V, McNerlan SE, Alexander HD, Ross OA (2018) Age and age-related diseases: role of inflammation triggers and cytokines. Front Immunol 9:586

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Tominaga K, Suzuki HI (2019) TGF-beta signaling in cellular senescence and aging-related pathology. Int J Mol Sci 20:5002

    Article  CAS  PubMed Central  Google Scholar 

  7. Roane BM, Arend RC, Birrer MJ (2019) Review: targeting the transforming growth factor-beta pathway in ovarian cancer. Cancers (Basel) 11:668

    Article  CAS  Google Scholar 

  8. Kumari A, Shonibare Z, Monavarian M, Arend RC, Lee NY, Inman GJ, Mythreye K (2021) TGFbeta signaling networks in ovarian cancer progression and plasticity. Clin Exp Metastasis 38:139–161

    Article  PubMed  PubMed Central  Google Scholar 

  9. Hinck AP, Mueller TD, Springer TA (2016) Structural biology and evolution of the TGF-beta family. Cold Spring Harb Perspect Biol 8:a022103

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Namwanje M, Brown CW (2016) Activins and inhibins: roles in development, physiology, and disease. Cold Spring Harb Perspect Biol 8:a021881

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Heldin CH, Moustakas A (2016) Signaling Receptors for TGF-beta Family Members. Cold Spring Harb Perspect Biol 8:a022053

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Assoian RK, Komoriya A, Meyers CA, Miller DM, Sporn MB (1983) Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization. J Biol Chem 258:7155–7160

    Article  CAS  PubMed  Google Scholar 

  13. Rifkin DB (2005) Latent transforming growth factor-beta (TGF-beta) binding proteins: orchestrators of TGF-beta availability. J Biol Chem 280:7409–7412

    Article  CAS  PubMed  Google Scholar 

  14. Murphy-Ullrich JE, Suto MJ (2018) Thrombospondin-1 regulation of latent TGF-beta activation: a therapeutic target for fibrotic disease. Matrix Biol 68–69:28–43

    Article  PubMed  CAS  Google Scholar 

  15. Nishimura SL (2009) Integrin-mediated transforming growth factor-beta activation, a potential therapeutic target in fibrogenic disorders. Am J Pathol 175:1362–1370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Amarnath S, Dong L, Li J, Wu Y, Chen W (2007) Endogenous TGF-beta activation by reactive oxygen species is key to Foxp3 induction in TCR-stimulated and HIV-1-infected human CD4+CD25- T cells. Retrovirology 4:57

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Tzavlaki K, Moustakas A (2020) TGF-beta signaling. Biomolecules 10:487

    Article  CAS  PubMed Central  Google Scholar 

  18. Wahl SM, McCartney-Francis N, Allen JB, Dougherty EB, Dougherty SF (1990) Macrophage production of TGF-beta and regulation by TGF-beta. Ann N Y Acad Sci 593:188–196

    Article  CAS  PubMed  Google Scholar 

  19. Grotendorst GR, Smale G, Pencev D (1989) Production of transforming growth factor beta by human peripheral blood monocytes and neutrophils. J Cell Physiol 140:396–402

    Article  CAS  PubMed  Google Scholar 

  20. Blakytny R, Ludlow A, Martin GE, Ireland G, Lund LR, Ferguson MW, Brunner G (2004) Latent TGF-beta1 activation by platelets. J Cell Physiol 199:67–76

    Article  CAS  PubMed  Google Scholar 

  21. Huang M, Sharma S, Zhu LX, Keane MP, Luo J, Zhang L, Burdick MD, Lin YQ, Dohadwala M, Gardner B, Batra RK, Strieter RM, Dubinett SM (2002) IL-7 inhibits fibroblast TGF-beta production and signaling in pulmonary fibrosis. J Clin Invest 109:931–937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ying WZ, Sanders PW (1999) Dietary salt increases endothelial nitric oxide synthase and TGF-beta1 in rat aortic endothelium. Am J Physiol 277:H1293–H1298

    CAS  PubMed  Google Scholar 

  23. Liu Y, Li Y, Li N, Teng W, Wang M, Zhang Y, Xiao Z (2016) TGF-beta1 promotes scar fibroblasts proliferation and transdifferentiation via up-regulating MicroRNA-21. Sci Rep 6:32231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lev PR, Salim JP, Marta RF, Osorio MJ, Goette NP, Molinas FC (2007) Platelets possess functional TGF-beta receptors and Smad2 protein. Platelets 18:35–42

    Article  CAS  PubMed  Google Scholar 

  25. Ksiazek K, Korybalska K, Jorres A, Witowski J (2007) Accelerated senescence of human peritoneal mesothelial cells exposed to high glucose: the role of TGF-beta1. Lab Invest 87:345–356

    Article  CAS  PubMed  Google Scholar 

  26. Yoshimura A, Muto G (2011) TGF-beta function in immune suppression. Curr Top Microbiol Immunol 350:127–147

    CAS  PubMed  Google Scholar 

  27. Huang SS, Huang JS (2005) TGF-beta control of cell proliferation. J Cell Biochem 96:447–462

    Article  CAS  PubMed  Google Scholar 

  28. Wang MK, Sun HQ, Xiang YC, Jiang F, Su YP, Zou ZM (2012) Different roles of TGF-beta in the multi-lineage differentiation of stem cells. World J Stem Cells 4:28–34

    Article  PubMed  PubMed Central  Google Scholar 

  29. Yoo J, Ghiassi M, Jirmanova L, Balliet AG, Hoffman B, Fornace AJ Jr, Liebermann DA, Bottinger EP, Roberts AB (2003) Transforming growth factor-beta-induced apoptosis is mediated by Smad-dependent expression of GADD45b through p38 activation. J Biol Chem 278:43001–43007

    Article  CAS  PubMed  Google Scholar 

  30. Moon JR, Oh SJ, Lee CK, Chi SG, Kim HJ (2019) TGF-beta1 protects colon tumor cells from apoptosis through XAF1 suppression. Int J Oncol 54:2117–2126

    CAS  PubMed  Google Scholar 

  31. Suzuki HI, Kiyono K, Miyazono K (2010) Regulation of autophagy by transforming growth factor-beta (TGF-beta) signaling. Autophagy 6:645–647

    Article  PubMed  Google Scholar 

  32. Casalena G, Daehn I, Bottinger E (2012) Transforming growth factor-beta, bioenergetics, and mitochondria in renal disease. Semin Nephrol 32:295–303

    Article  CAS  PubMed  Google Scholar 

  33. Yoon YS, Lee JH, Hwang SC, Choi KS, Yoon G (2005) TGF beta1 induces prolonged mitochondrial ROS generation through decreased complex IV activity with senescent arrest in Mv1Lu cells. Oncogene 24:1895–1903

    Article  CAS  PubMed  Google Scholar 

  34. Kariya T, Nishimura H, Mizuno M, Suzuki Y, Matsukawa Y, Sakata F, Maruyama S, Takei Y, Ito Y (2018) TGF-beta1-VEGF-A pathway induces neoangiogenesis with peritoneal fibrosis in patients undergoing peritoneal dialysis. Am J Physiol Renal Physiol 314:F167–F180

    Article  PubMed  CAS  Google Scholar 

  35. Hocevar BA, Brown TL, Howe PH (1999) TGF-beta induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway. EMBO J 18:1345–1356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lim JY, Park SJ, Hwang HY, Park EJ, Nam JH, Kim J, Park SI (2005) TGF-beta1 induces cardiac hypertrophic responses via PKC-dependent ATF-2 activation. J Mol Cell Cardiol 39:627–636

    Article  CAS  PubMed  Google Scholar 

  37. Frangogiannis N (2020) Transforming growth factor-beta in tissue fibrosis. J Exp Med 217:e20190103

    Article  PubMed  PubMed Central  Google Scholar 

  38. Cheng H, Jiang W, Phillips FM, Haydon RC, Peng Y, Zhou L, Luu HH, An N, Breyer B, Vanichakarn P, Szatkowski JP, Park JY, He TC (2003) Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs). J Bone Joint Surg Am 85:1544–1552

    Article  PubMed  Google Scholar 

  39. Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA (1988) Novel regulators of bone formation: molecular clones and activities. Science 242:1528–1534

    Article  CAS  PubMed  Google Scholar 

  40. Suzuki Y, Montagne K, Nishihara A, Watabe T, Miyazono K (2008) BMPs promote proliferation and migration of endothelial cells via stimulation of VEGF-A/VEGFR2 and angiopoietin-1/Tie2 signalling. J Biochem 143:199–206

    Article  CAS  PubMed  Google Scholar 

  41. Chen D, Ji X, Harris MA, Feng JQ, Karsenty G, Celeste AJ, Rosen V, Mundy GR, Harris SE (1998) Differential roles for bone morphogenetic protein (BMP) receptor type IB and IA in differentiation and specification of mesenchymal precursor cells to osteoblast and adipocyte lineages. J Cell Biol 142:295–305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Massague J (2008) TGFbeta in Cancer. Cell 134:215–230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kim BN, Ahn DH, Kang N, Yeo CD, Kim YK, Lee KY, Kim TJ, Lee SH, Park MS, Yim HW, Park JY, Park CK, Kim SJ (2020) TGF-beta induced EMT and stemness characteristics are associated with epigenetic regulation in lung cancer. Sci Rep 10:10597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bhagyaraj E, Ahuja N, Kumar S, Tiwari D, Gupta S, Nanduri R, Gupta P (2019) TGF-beta induced chemoresistance in liver cancer is modulated by xenobiotic nuclear receptor PXR. Cell Cycle 18:3589–3602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Barrett CS, Millena AC, Khan SA (2017) TGF-beta effects on prostate cancer cell migration and invasion require FosB. Prostate 77:72–81

    Article  CAS  PubMed  Google Scholar 

  46. Pang MF, Georgoudaki AM, Lambut L, Johansson J, Tabor V, Hagikura K, Jin Y, Jansson M, Alexander JS, Nelson CM, Jakobsson L, Betsholtz C, Sund M, Karlsson MC, Fuxe J (2016) TGF-beta1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis. Oncogene 35:748–760

    Article  CAS  PubMed  Google Scholar 

  47. Angioni R, Sanchez-Rodriguez R, Viola A, Molon B (2021) TGF-beta in cancer: metabolic driver of the tolerogenic crosstalk in the tumor microenvironment. Cancers (Basel) 13:401

    Article  CAS  Google Scholar 

  48. Steiner MS, Barrack ER (1992) Transforming growth factor-beta 1 overproduction in prostate cancer: effects on growth in vivo and in vitro. Mol Endocrinol 6:15–25

    CAS  PubMed  Google Scholar 

  49. Nakamura S, Kawai T, Kamakura T, Ookura T (2010) TGF-beta3 is expressed in taste buds and inhibits proliferation of primary cultured taste epithelial cells. In Vitro Cell Dev Biol Anim 46:36–44

    Article  CAS  PubMed  Google Scholar 

  50. Liu H, Zhu Y, Zhu H, Cai R, Wang KF, Song J, Wang RX, Zhou RX (2019) Role of transforming growth factor beta1 in the inhibition of gastric cancer cell proliferation by melatonin in vitro and in vivo. Oncol Rep 42:753–762

    CAS  PubMed  Google Scholar 

  51. Li H, Xu D, Li J, Berndt MC, Liu JP (2006) Transforming growth factor beta suppresses human telomerase reverse transcriptase (hTERT) by Smad3 interactions with c-Myc and the hTERT gene. J Biol Chem 281:25588–25600

    Article  CAS  PubMed  Google Scholar 

  52. Mikula-Pietrasik J, Niklas A, Uruski P, Tykarski A, Ksiazek K (2020) Mechanisms and significance of therapy-induced and spontaneous senescence of cancer cells. Cell Mol Life Sci 77:213–229

    Article  CAS  PubMed  Google Scholar 

  53. Zhang L, Ye Y, Long X, Xiao P, Ren X, Yu J (2016) BMP signaling and its paradoxical effects in tumorigenesis and dissemination. Oncotarget 7:78206–78218

    Article  PubMed  PubMed Central  Google Scholar 

  54. Virk MS, Petrigliano FA, Liu NQ, Chatziioannou AF, Stout D, Kang CO, Dougall WC, Lieberman JR (2009) Influence of simultaneous targeting of the bone morphogenetic protein pathway and RANK/RANKL axis in osteolytic prostate cancer lesion in bone. Bone 44:160–167

    Article  CAS  PubMed  Google Scholar 

  55. Busch C, Drews U, Eisele SR, Garbe C, Oppitz M (2008) Noggin blocks invasive growth of murine B16–F1 melanoma cells in the optic cup of the chick embryo. Int J Cancer 122:526–533

    Article  CAS  PubMed  Google Scholar 

  56. Langenfeld EM, Calvano SE, Abou-Nukta F, Lowry SF, Amenta P, Langenfeld J (2003) The mature bone morphogenetic protein-2 is aberrantly expressed in non-small cell lung carcinomas and stimulates tumor growth of A549 cells. Carcinogenesis 24:1445–1454

    Article  CAS  PubMed  Google Scholar 

  57. Buckley S, Shi W, Driscoll B, Ferrario A, Anderson K, Warburton D (2004) BMP4 signaling induces senescence and modulates the oncogenic phenotype of A549 lung adenocarcinoma cells. Am J Physiol Lung Cell Mol Physiol 286:L81–L86

    Article  CAS  PubMed  Google Scholar 

  58. Dai Z, Popkie AP, Zhu WG, Timmers CD, Raval A, Tannehill-Gregg S, Morrison CD, Auer H, Kratzke RA, Niehans G, Amatschek S, Sommergruber W, Leone GW, Rosol T, Otterson GA, Plass C (2004) Bone morphogenetic protein 3B silencing in non-small-cell lung cancer. Oncogene 23:3521–3529

    Article  CAS  PubMed  Google Scholar 

  59. Bach DH, Park HJ, Lee SK (2018) The dual role of bone morphogenetic proteins in cancer. Mol Ther Oncolytics 8:1–13

    Article  PubMed  CAS  Google Scholar 

  60. Rattan SI (2004) Aging, anti-aging, and hormesis. Mech Ageing Dev 125:285–289

    Article  CAS  PubMed  Google Scholar 

  61. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A (2018) Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol 14:576–590

    Article  CAS  PubMed  Google Scholar 

  62. Aiello A, Farzaneh F, Candore G, Caruso C, Davinelli S, Gambino CM, Ligotti ME, Zareian N, Accardi G (2019) Immunosenescence and its hallmarks: how to oppose aging strategically? A review of potential options for therapeutic intervention. Front Immunol 10:2247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhao H, Zhang H, Qin X (2017) Age-related differences in serum MFGE8, TGFbeta1 and correlation to the severity of atherosclerosis determined by ultrasound. Mol Med Rep 16:9741–9748

    Article  CAS  PubMed  Google Scholar 

  64. Okamoto Y, Gotoh Y, Uemura O, Tanaka S, Ando T, Nishida M (2005) Age-dependent decrease in serum transforming growth factor (TGF)-beta 1 in healthy Japanese individuals; population study of serum TGF-beta 1 level in Japanese. Dis Markers 21:71–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Forsey RJ, Thompson JM, Ernerudh J, Hurst TL, Strindhall J, Johansson B, Nilsson BO, Wikby A (2003) Plasma cytokine profiles in elderly humans. Mech Ageing Dev 124:487–493

    Article  CAS  PubMed  Google Scholar 

  66. Salvioli S, Capri M, Bucci L, Lanni C, Racchi M, Uberti D, Memo M, Mari D, Govoni S, Franceschi C (2009) Why do centenarians escape or postpone cancer? The role of IGF-1, inflammation and p53. Cancer Immunol Immunother 58:1909–1917

    Article  CAS  PubMed  Google Scholar 

  67. Meyers EA, Gobeske KT, Bond AM, Jarrett JC, Peng CY, Kessler JA (2016) Increased bone morphogenetic protein signaling contributes to age-related declines in neurogenesis and cognition. Neurobiol Aging 38:164–175

    Article  CAS  PubMed  Google Scholar 

  68. Carrieri G, Marzi E, Olivieri F, Marchegiani F, Cavallone L, Cardelli M, Giovagnetti S, Stecconi R, Molendini C, Trapassi C, De Benedictis G, Kletsas D, Franceschi C (2004) The G/C915 polymorphism of transforming growth factor beta1 is associated with human longevity: a study in Italian centenarians. Aging Cell 3:443–448

    Article  CAS  PubMed  Google Scholar 

  69. Ruberto S, Santovito A (2021) Association of TGFbeta1 codon 10 (T>C) and IL-10 (G>C) cytokine gene polymorphisms with longevity in a cohort of Italian population. Am J Hum Biol 33:e23491

    Article  PubMed  Google Scholar 

  70. Awad MR, El-Gamel A, Hasleton P, Turner DM, Sinnott PJ, Hutchinson IV (1998) Genotypic variation in the transforming growth factor-beta1 gene: association with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. Transplantation 66:1014–1020

    Article  CAS  PubMed  Google Scholar 

  71. Blaney Davidson EN, Remst DF, Vitters EL, van Beuningen HM, Blom AB, Goumans MJ, van den Berg WB, van der Kraan PM (2009) Increase in ALK1/ALK5 ratio as a cause for elevated MMP-13 expression in osteoarthritis in humans and mice. J Immunol 182:7937–7945

    Article  CAS  PubMed  Google Scholar 

  72. Hui W, Young DA, Rowan AD, Xu X, Cawston TE, Proctor CJ (2016) Oxidative changes and signalling pathways are pivotal in initiating age-related changes in articular cartilage. Ann Rheum Dis 75:449–458

    Article  CAS  PubMed  Google Scholar 

  73. Hodgson D, Rowan AD, Falciani F, Proctor CJ (2019) Systems biology reveals how altered TGFbeta signalling with age reduces protection against pro-inflammatory stimuli. PLoS Comput Biol 15:e1006685

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Xia S, Zhang X, Zheng S, Khanabdali R, Kalionis B, Wu J, Wan W, Tai X (2016) An update on inflamm-aging: mechanisms, prevention, and treatment. J Immunol Res 2016:8426874

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Faget DV, Ren Q, Stewart SA (2019) Unmasking senescence: context-dependent effects of SASP in cancer. Nat Rev Cancer 19:439–453

    Article  CAS  PubMed  Google Scholar 

  76. Mikula-Pietrasik J, Stryczynski L, Uruski P, Tykarski A, Ksiazek K (2018) Procancerogenic activity of senescent cells: a case of the peritoneal mesothelium. Ageing Res Rev 43:1–9

    Article  CAS  PubMed  Google Scholar 

  77. Coppe JP, Desprez PY, Krtolica A, Campisi J (2010) The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 5:99–118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Vande Berg JS, Rose MA, Haywood-Reid PL, Rudolph R, Payne WG, Robson MC (2005) Cultured pressure ulcer fibroblasts show replicative senescence with elevated production of plasmin, plasminogen activator inhibitor-1, and transforming growth factor-beta1. Wound Repair Regen 13:76–83

    Article  PubMed  Google Scholar 

  79. Pascal T, Debacq-Chainiaux F, Chretien A, Bastin C, Dabee AF, Bertholet V, Remacle J, Toussaint O (2005) Comparison of replicative senescence and stress-induced premature senescence combining differential display and low-density DNA arrays. FEBS Lett 579:3651–3659

    Article  CAS  PubMed  Google Scholar 

  80. Shelton DN, Chang E, Whittier PS, Choi D, Funk WD (1999) Microarray analysis of replicative senescence. Curr Biol 9:939–945

    Article  CAS  PubMed  Google Scholar 

  81. Lee MY, Wang Y, Vanhoutte PM (2010) Senescence of cultured porcine coronary arterial endothelial cells is associated with accelerated oxidative stress and activation of NFkB. J Vasc Res 47:287–298

    Article  CAS  PubMed  Google Scholar 

  82. Tremain R, Marko M, Kinnimulki V, Ueno H, Bottinger E, Glick A (2000) Defects in TGF-beta signaling overcome senescence of mouse keratinocytes expressing v-Ha-ras. Oncogene 19:1698–1709

    Article  CAS  PubMed  Google Scholar 

  83. Mikula-Pietrasik J, Sosinska P, Janus J, Rubis B, Brewinska-Olchowik M, Piwocka K, Ksiazek K (2013) Bystander senescence in human peritoneal mesothelium and fibroblasts is related to thrombospondin-1-dependent activation of transforming growth factor-beta1. Int J Biochem Cell Biol 45:2087–2096

    Article  CAS  PubMed  Google Scholar 

  84. Rapisarda V, Borghesan M, Miguela V, Encheva V, Snijders AP, Lujambio A, O’Loghlen A (2017) Integrin beta 3 regulates cellular senescence by activating the TGF-beta pathway. Cell Rep 18:2480–2493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Hassona Y, Cirillo N, Lim KP, Herman A, Mellone M, Thomas GJ, Pitiyage GN, Parkinson EK, Prime SS (2013) Progression of genotype-specific oral cancer leads to senescence of cancer-associated fibroblasts and is mediated by oxidative stress and TGF-beta. Carcinogenesis 34:1286–1295

    Article  CAS  PubMed  Google Scholar 

  86. Campisi J (1997) Aging and cancer: the double-edged sword of replicative senescence. J Am Geriatr Soc 45:482–488

    Article  CAS  PubMed  Google Scholar 

  87. Frippiat C, Chen QM, Zdanov S, Magalhaes JP, Remacle J, Toussaint O (2001) Subcytotoxic H2O2 stress triggers a release of transforming growth factor-beta 1, which induces biomarkers of cellular senescence of human diploid fibroblasts. J Biol Chem 276:2531–2537

    Article  CAS  PubMed  Google Scholar 

  88. Ksiazek K, Mikula-Pietrasik J, Jorres A, Witowski J (2008) Oxidative stress-mediated early senescence contributes to the short replicative life span of human peritoneal mesothelial cells. Free Radic Biol Med 45:460–467

    Article  CAS  PubMed  Google Scholar 

  89. Mellone M, Hanley CJ, Thirdborough S, Mellows T, Garcia E, Woo J, Tod J, Frampton S, Jenei V, Moutasim KA, Kabir TD, Brennan PA, Venturi G, Ford K, Herranz N, Lim KP, Clarke J, Lambert DW, Prime SS, Underwood TJ, Vijayanand P, Eliceiri KW, Woelk C, King EV, Gil J, Ottensmeier CH, Thomas GJ (2016) Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis. Aging (Albany NY) 9:114–132

    Article  Google Scholar 

  90. Untergasser G, Gander R, Rumpold H, Heinrich E, Plas E, Berger P (2003) TGF-beta cytokines increase senescence-associated beta-galactosidase activity in human prostate basal cells by supporting differentiation processes, but not cellular senescence. Exp Gerontol 38:1179–1188

    Article  CAS  PubMed  Google Scholar 

  91. Ksiazek K, Mikula-Pietrasik J, Korybalska K, Dworacki G, Jorres A, Witowski J (2009) Senescent peritoneal mesothelial cells promote ovarian cancer cell adhesion: the role of oxidative stress-induced fibronectin. Am J Pathol 174:1230–1240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Iglesias-De La Cruz MC, Ruiz-Torres P, Alcami J, Diez-Marques L, Ortega-Velazquez R, Chen S, Rodriguez-Puyol M, Ziyadeh FN, Rodriguez-Puyol D (2001) Hydrogen peroxide increases extracellular matrix mRNA through TGF-beta in human mesangial cells. Kidney Int 59:87–95

    Article  CAS  PubMed  Google Scholar 

  93. Kretova M, Sabova L, Hodny Z, Bartek J, Kollarovic G, Nelson BD, Hubackova S, Luciakova K (2014) TGF-beta/NF1/Smad4-mediated suppression of ANT2 contributes to oxidative stress in cellular senescence. Cell Signal 26:2903–2911

    Article  CAS  PubMed  Google Scholar 

  94. Wu J, Niu J, Li X, Wang X, Guo Z, Zhang F (2014) TGF-beta1 induces senescence of bone marrow mesenchymal stem cells via increase of mitochondrial ROS production. BMC Dev Biol 14:21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Son Y, Cheong YK, Kim NH, Chung HT, Kang DG, Pae HO (2011) Mitogen-activated protein kinases and reactive oxygen species: how can ROS activate MAPK pathways? J Signal Transduct 2011:792639

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Książek K, Winckiewicz M, Staniszewski R, Breborowicz A, Witowski J (2007) Correlation between the donor age and the proliferative lifespan of human peritoneal mesothelial cells in vitro: is TGF-beta1 a link? Exp Gerontol 42:840–843

    Article  PubMed  CAS  Google Scholar 

  97. Sosinska P, Mikula-Pietrasik J, Ryzek M, Naumowicz E, Ksiazek K (2014) Specificity of cytochemical and fluorescence methods of senescence-associated beta-galactosidase detection for ageing driven by replication and time. Biogerontology 15:407–413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Gong C, Pan W, Hu W, Chen L (2019) Bone morphogenetic protein-7 retards cell subculture-induced senescence of human nucleus pulposus cells through activating the PI3K/Akt pathway. Biosci Rep 39:BSR20182312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hayashi Y, Hsiao EC, Sami S, Lancero M, Schlieve CR, Nguyen T, Yano K, Nagahashi A, Ikeya M, Matsumoto Y, Nishimura K, Fukuda A, Hisatake K, Tomoda K, Asaka I, Toguchida J, Conklin BR, Yamanaka S (2016) BMP-SMAD-ID promotes reprogramming to pluripotency by inhibiting p16/INK4A-dependent senescence. Proc Natl Acad Sci USA 113:13057–13062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Zhu D, Wu J, Spee C, Ryan SJ, Hinton DR (2009) BMP4 mediates oxidative stress-induced retinal pigment epithelial cell senescence and is overexpressed in age-related macular degeneration. J Biol Chem 284:9529–9539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Su D, Zhu S, Han X, Feng Y, Huang H, Ren G, Pan L, Zhang Y, Lu J, Huang B (2009) BMP4-Smad signaling pathway mediates adriamycin-induced premature senescence in lung cancer cells. J Biol Chem 284:12153–12164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300

    Article  PubMed  Google Scholar 

  103. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  104. Marsh T, Pietras K, McAllister SS (2013) Fibroblasts as architects of cancer pathogenesis. Biochim Biophys Acta 1832:1070–1078

    Article  CAS  PubMed  Google Scholar 

  105. Guan X, LaPak KM, Hennessey RC, Yu CY, Shakya R, Zhang J, Burd CE (2017) Stromal senescence by prolonged CDK4/6 inhibition potentiates tumor growth. Mol Cancer Res 15:237–249

    Article  CAS  PubMed  Google Scholar 

  106. Liu D, Hornsby PJ (2007) Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. Cancer Res 67:3117–3126

    Article  CAS  PubMed  Google Scholar 

  107. Taddei ML, Cavallini L, Comito G, Giannoni E, Folini M, Marini A, Gandellini P, Morandi A, Pintus G, Raspollini MR, Zaffaroni N, Chiarugi P (2014) Senescent stroma promotes prostate cancer progression: the role of miR-210. Mol Oncol 8:1729–1746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Papadopoulou A, Kletsas D (2011) Human lung fibroblasts prematurely senescent after exposure to ionizing radiation enhance the growth of malignant lung epithelial cells in vitro and in vivo. Int J Oncol 39:989–999

    CAS  PubMed  Google Scholar 

  109. Wang T, Notta F, Navab R, Joseph J, Ibrahimov E, Xu J, Zhu CQ, Borgida A, Gallinger S, Tsao MS (2017) Senescent carcinoma-associated fibroblasts upregulate IL8 to enhance prometastatic phenotypes. Mol Cancer Res 15:3–14

    Article  CAS  PubMed  Google Scholar 

  110. Mikula-Pietrasik J, Sosinska P, Maksin K, Kucinska MG, Piotrowska H, Murias M, Wozniak A, Szpurek D, Ksiazek K (2015) Colorectal cancer-promoting activity of the senescent peritoneal mesothelium. Oncotarget 6:29178–29195

    Article  PubMed  PubMed Central  Google Scholar 

  111. Mikula-Pietrasik J, Uruski P, Sosinska P, Maksin K, Piotrowska-Kempisty H, Kucinska M, Murias M, Szubert S, Wozniak A, Szpurek D, Sajdak S, Piwocka K, Tykarski A, Ksiazek K (2016) Senescent peritoneal mesothelium creates a niche for ovarian cancer metastases. Cell Death Dis 7:e2565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Gonzalez-Meljem JM, Haston S, Carreno G, Apps JR, Pozzi S, Stache C, Kaushal G, Virasami A, Panousopoulos L, Mousavy-Gharavy SN, Guerrero A, Rashid M, Jani N, Goding CR, Jacques TS, Adams DJ, Gil J, Andoniadou CL, Martinez-Barbera JP (2017) Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma. Nat Commun 8:1819

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Buhl JL, Selt F, Hielscher T, Guiho R, Ecker J, Sahm F, Ridinger J, Riehl D, Usta D, Ismer B, Sommerkamp AC, Martinez-Barbera JP, Wefers AK, Remke M, Picard D, Pusch S, Gronych J, Oehme I, van Tilburg CM, Kool M, Kuhn D, Capper D, von Deimling A, Schuhmann MU, Herold-Mende C, Korshunov A, Brummer T, Pfister SM, Jones DTW, Witt O, Milde T (2019) The senescence-associated secretory phenotype mediates oncogene-induced senescence in pediatric pilocytic astrocytoma. Clin Cancer Res 25:1851–1866

    Article  CAS  PubMed  Google Scholar 

  114. Javadi S, Ganeshan DM, Qayyum A, Iyer RB, Bhosale P (2016) Ovarian cancer, the revised FIGO staging system, and the role of imaging. AJR Am J Roentgenol 206:1351–1360

    Article  PubMed  Google Scholar 

  115. Hunn J, Rodriguez GC (2012) Ovarian cancer: etiology, risk factors, and epidemiology. Clin Obstet Gynecol 55:3–23

    Article  PubMed  Google Scholar 

  116. Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, Gaudet MM, Jemal A, Siegel RL (2018) Ovarian cancer statistics, 2018. CA Cancer J Clin 68:284–296

    Article  PubMed  PubMed Central  Google Scholar 

  117. Farsinejad S, Cattabiani T, Muranen T, Iwanicki M (2019) Ovarian cancer dissemination-a cell biologist’s perspective. Cancers (Basel) 11:1957

    Article  CAS  Google Scholar 

  118. Lengyel E (2010) Ovarian cancer development and metastasis. Am J Pathol 177:1053–1064

    Article  PubMed  PubMed Central  Google Scholar 

  119. Amadori D, Sansoni E, Amadori A (1997) Ovarian cancer: natural history and metastatic pattern. Front Biosci 2:g8-10

    CAS  PubMed  Google Scholar 

  120. Pickel H, Lahousen M, Girardi F, Tamussino H, Stettner H (1990) Intraperitoneal and retroperitoneal spread of ovarian cancer. In: Sharp C, Mason W, Leake R (eds) Ovarian cancer: biologic and therapeutic challenges. Chapman and Hall, London

    Google Scholar 

  121. Kenny HA, Chiang CY, White EA, Schryver EM, Habis M, Romero IL, Ladanyi A, Penicka CV, George J, Matlin K, Montag A, Wroblewski K, Yamada SD, Mazar AP, Bowtell D, Lengyel E (2014) Mesothelial cells promote early ovarian cancer metastasis through fibronectin secretion. J Clin Invest 124:4614–4628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Janiszewska M, Primi MC, Izard T (2020) Cell adhesion in cancer: Beyond the migration of single cells. J Biol Chem 295:2495–2505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Kenny HA, Krausz T, Yamada SD, Lengyel E (2007) Use of a novel 3D culture model to elucidate the role of mesothelial cells, fibroblasts and extra-cellular matrices on adhesion and invasion of ovarian cancer cells to the omentum. Int J Cancer 121:1463–1472

    Article  CAS  PubMed  Google Scholar 

  124. Mikula-Pietrasik J, Sosinska P, Kucinska M, Murias M, Maksin K, Malinska A, Ziolkowska A, Piotrowska H, Wozniak A, Ksiazek K (2014) Peritoneal mesothelium promotes the progression of ovarian cancer cells in vitro and in a mice xenograft model in vivo. Cancer Lett 355:310–315

    Article  CAS  PubMed  Google Scholar 

  125. Uruski P, Mikula-Pietrasik J, Pakula M, Budkiewicz S, Drzewiecki M, Gaiday AN, Wierzowiecka M, Naumowicz E, Moszynski R, Tykarski A, Ksiazek K (2021) Malignant ascites promote adhesion of ovarian cancer cells to peritoneal mesothelium and fibroblasts. Int J Mol Sci 22:4222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Smolle E, Taucher V, Haybaeck J (2014) Malignant ascites in ovarian cancer and the role of targeted therapeutics. Anticancer Res 34:1553–1561

    CAS  PubMed  Google Scholar 

  127. Damen MPF, van Rheenen J, Scheele C (2021) Targeting dormant tumor cells to prevent cancer recurrence. FEBS J 288:6286–6303

    Article  CAS  PubMed  Google Scholar 

  128. Barney LE, Hall CL, Schwartz AD, Parks AN, Sparages C, Galarza S, Platt MO, Mercurio AM, Peyton SR (2020) Tumor cell-organized fibronectin maintenance of a dormant breast cancer population. Sci Adv 6:eaaz4157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Cavallaro U, Christofori G (2001) Cell adhesion in tumor invasion and metastasis: loss of the glue is not enough. Biochim Biophys Acta 1552:39–45

    CAS  PubMed  Google Scholar 

  130. Cirillo N, Hassona Y, Celentano A, Lim KP, Manchella S, Parkinson EK, Prime SS (2017) Cancer-associated fibroblasts regulate keratinocyte cell-cell adhesion via TGF-beta-dependent pathways in genotype-specific oral cancer. Carcinogenesis 38:76–85

    Article  CAS  PubMed  Google Scholar 

  131. Stuelten CH, Parent CA, Montell DJ (2018) Cell motility in cancer invasion and metastasis: insights from simple model organisms. Nat Rev Cancer 18:296–312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Oh E, Quartuccio SM, Cheng W, Ahmed RA, King SM, Burdette JE (2014) Mutation or loss of p53 differentially modifies TGFbeta action in ovarian cancer. PLoS One 9:e89553

    Article  CAS  Google Scholar 

  133. Pakula M, Witucka A, Uruski P, Radziemski A, Moszynski R, Szpurek D, Maksin K, Wozniak A, Sajdak S, Tykarski A, Mikula-Pietrasik J, Ksiazek K (2019) Senescence-related deterioration of intercellular junctions in the peritoneal mesothelium promotes the transmesothelial invasion of ovarian cancer cells. Sci Rep 9:7587

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Hassona Y, Cirillo N, Heesom K, Parkinson EK, Prime SS (2014) Senescent cancer-associated fibroblasts secrete active MMP-2 that promotes keratinocyte dis-cohesion and invasion. Br J Cancer 111:1230–1237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Lin SW, Ke FC, Hsiao PW, Lee PP, Lee MT, Hwang JJ (2007) Critical involvement of ILK in TGFbeta1-stimulated invasion/migration of human ovarian cancer cells is associated with urokinase plasminogen activator system. Exp Cell Res 313:602–613

    Article  CAS  PubMed  Google Scholar 

  136. Yu Q, Stamenkovic I (2000) Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 14:163–176

    Article  PubMed  PubMed Central  Google Scholar 

  137. Melzer C, von der Ohe J, Hass R, Ungefroren H (2017) TGF-beta-dependent growth arrest and cell migration in benign and malignant breast epithelial cells are antagonistically controlled by Rac1 and Rac1b. Int J Mol Sci 18:1574

    Article  PubMed Central  CAS  Google Scholar 

  138. Lin S, Yang J, Elkahloun AG, Bandyopadhyay A, Wang L, Cornell JE, Yeh IT, Agyin J, Tomlinson G, Sun LZ (2012) Attenuation of TGF-beta signaling suppresses premature senescence in a p21-dependent manner and promotes oncogenic Ras-mediated metastatic transformation in human mammary epithelial cells. Mol Biol Cell 23:1569–1581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Lin HK, Bergmann S, Pandolfi PP (2004) Cytoplasmic PML function in TGF-beta signalling. Nature 431:205–211

    Article  CAS  PubMed  Google Scholar 

  140. Tanabe Y, Kawamoto S, Takaku T, Morishita S, Hirao A, Komatsu N, Hara E, Mukaida N, Baba T (2020) Expansion of senescent megakaryocyte-lineage cells maintains CML cell leukemogenesis. Blood Adv 4:6175–6188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Mittal V (2018) Epithelial mesenchymal transition in tumor metastasis. Annu Rev Pathol 13:395–412

    Article  CAS  PubMed  Google Scholar 

  142. Terri M, Trionfetti F, Montaldo C, Cordani M, Tripodi M, Lopez-Cabrera M, Strippoli R (2021) Mechanisms of peritoneal fibrosis: focus on immune cells-peritoneal stroma interactions. Front Immunol 12:607204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Hao Y, Baker D, Ten Dijke P (2019) TGF-beta-mediated epithelial-mesenchymal transition and cancer metastasis. Int J Mol Sci 20:2767

    Article  CAS  PubMed Central  Google Scholar 

  144. Guan T, Dominguez CX, Amezquita RA, Laidlaw BJ, Cheng J, Henao-Mejia J, Williams A, Flavell RA, Lu J, Kaech SM (2018) ZEB1, ZEB2, and the miR-200 family form a counterregulatory network to regulate CD8(+) T cell fates. J Exp Med 215:1153–1168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Yu L, Cao C, Li X, Zhang M, Gu Q, Gao H, Balic JJ, Xu D, Zhang L, Ying L, Xu D, Yang Y, Wu D, He B, Jenkins BJ, Liu Y, Li J (2021) Complete loss of miR-200 family induces EMT associated cellular senescence in gastric cancer. Oncogene 41(1):26–36

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Kidan N, Khamaisie H, Ruimi N, Roitman S, Eshel E, Dally N, Ruthardt M, Mahajna J (2017) Ectopic expression of snail and twist in Ph+ leukemia cells upregulates CD44 expression and alters their differentiation potential. J Cancer 8:3952–3968

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Pakula M, Uruski P, Niklas A, Wozniak A, Szpurek D, Tykarski A, Mikula-Pietrasik J, Ksiazek K (2019) A unique pattern of mesothelial-mesenchymal transition induced in the normal peritoneal mesothelium by high-grade serous ovarian cancer. Cancers (Basel) 11:662

    Article  CAS  Google Scholar 

  148. Sandoval P, Jimenez-Heffernan JA, Rynne-Vidal A, Perez-Lozano ML, Gilsanz A, Ruiz-Carpio V, Reyes R, Garcia-Bordas J, Stamatakis K, Dotor J, Majano PL, Fresno M, Cabanas C, Lopez-Cabrera M (2013) Carcinoma-associated fibroblasts derive from mesothelial cells via mesothelial-to-mesenchymal transition in peritoneal metastasis. J Pathol 231:517–531

    Article  CAS  PubMed  Google Scholar 

  149. Rynne-Vidal A, Au-Yeung CL, Jimenez-Heffernan JA, Perez-Lozano ML, Cremades-Jimeno L, Barcena C, Cristobal-Garcia I, Fernandez-Chacon C, Yeung TL, Mok SC, Sandoval P, Lopez-Cabrera M (2017) Mesothelial-to-mesenchymal transition as a possible therapeutic target in peritoneal metastasis of ovarian cancer. J Pathol 242:140–151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Smit MA, Peeper DS (2010) Epithelial-mesenchymal transition and senescence: two cancer-related processes are crossing paths. Aging (Albany NY) 2:735–741

    Article  CAS  Google Scholar 

  151. Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J, Beug H, Grunert S (2002) Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 156:299–313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88:593–602

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  154. Augsten M (2014) Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment. Front Oncol 4:62

    Article  PubMed  PubMed Central  Google Scholar 

  155. Tan ML, Parkinson EK, Yap LF, Paterson IC (2021) Autophagy is deregulated in cancer-associated fibroblasts from oral cancer and is stimulated during the induction of fibroblast senescence by TGF-beta1. Sci Rep 11:584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, Washington MK, Neilson EG, Moses HL (2004) TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303:848–851

    Article  CAS  PubMed  Google Scholar 

  157. Calon A, Espinet E, Palomo-Ponce S, Tauriello DV, Iglesias M, Cespedes MV, Sevillano M, Nadal C, Jung P, Zhang XH, Byrom D, Riera A, Rossell D, Mangues R, Massague J, Sancho E, Batlle E (2012) Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell 22:571–584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Cai J, Tang H, Xu L, Wang X, Yang C, Ruan S, Guo J, Hu S, Wang Z (2012) Fibroblasts in omentum activated by tumor cells promote ovarian cancer growth, adhesion and invasiveness. Carcinogenesis 33:20–29

    Article  CAS  PubMed  Google Scholar 

  159. Lugano R, Ramachandran M, Dimberg A (2020) Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci 77:1745–1770

    Article  CAS  PubMed  Google Scholar 

  160. Coppe JP, Kauser K, Campisi J, Beausejour CM (2006) Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J Biol Chem 281:29568–29574

    Article  CAS  PubMed  Google Scholar 

  161. Mikula-Pietrasik J, Sosinska P, Naumowicz E, Maksin K, Piotrowska H, Wozniak A, Szpurek D, Ksiazek K (2016) Senescent peritoneal mesothelium induces a pro-angiogenic phenotype in ovarian cancer cells in vitro and in a mouse xenograft model in vivo. Clin Exp Metastasis 33:15–27

    Article  CAS  PubMed  Google Scholar 

  162. Kay EP, Lee MS, Seong GJ, Lee YG (1998) TGF-beta s stimulate cell proliferation via an autocrine production of FGF-2 in corneal stromal fibroblasts. Curr Eye Res 17:286–293

    Article  CAS  PubMed  Google Scholar 

  163. Heredia-Soto V, Lopez-Guerrero JA, Redondo A, Mendiola M (2020) The hallmarks of ovarian cancer: Focus on angiogenesis and micro-environment and new models for their characterisation. EJC Suppl 15:49–55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Gerber SA, Rybalko VY, Bigelow CE, Lugade AA, Foster TH, Frelinger JG, Lord EM (2006) Preferential attachment of peritoneal tumor metastases to omental immune aggregates and possible role of a unique vascular microenvironment in metastatic survival and growth. Am J Pathol 169:1739–1752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Bai H, Gao Y, Hoyle DL, Cheng T, Wang ZZ (2017) Suppression of transforming growth factor-beta signaling delays cellular senescence and preserves the function of endothelial cells derived from human pluripotent stem cells. Stem Cells Transl Med 6:589–600

    Article  PubMed  CAS  Google Scholar 

  166. Blanco FJ, Grande MT, Langa C, Oujo B, Velasco S, Rodriguez-Barbero A, Perez-Gomez E, Quintanilla M, Lopez-Novoa JM, Bernabeu C (2008) S-endoglin expression is induced in senescent endothelial cells and contributes to vascular pathology. Circ Res 103:1383–1392

    Article  CAS  PubMed  Google Scholar 

  167. Krugmann J, Schwarz CL, Melcher B, Sterlacci W, Ozalinskaite A, Lermann J, Agaimy A, Vieth M (2019) Malignant ascites occurs most often in patients with high-grade serous papillary ovarian cancer at initial diagnosis: a retrospective analysis of 191 women treated at Bayreuth Hospital, 2006–2015. Arch Gynecol Obstet 299:515–523

    Article  CAS  PubMed  Google Scholar 

  168. Adam RA, Adam YG (2004) Malignant ascites: past, present, and future. J Am Coll Surg 198:999–1011

    Article  PubMed  Google Scholar 

  169. Mikula-Pietrasik J, Uruski P, Matuszkiewicz K, Szubert S, Moszynski R, Szpurek D, Sajdak S, Tykarski A, Ksiazek K (2016) Ovarian cancer-derived ascitic fluids induce a senescence-dependent pro-cancerogenic phenotype in normal peritoneal mesothelial cells. Cell Oncol (Dordr ) 39:473–481

    Article  CAS  Google Scholar 

  170. Mikula-Pietrasik J, Uruski P, Szubert S, Moszynski R, Szpurek D, Sajdak S, Tykarski A, Ksiazek K (2016) Biochemical composition of malignant ascites determines high aggressiveness of undifferentiated ovarian tumors. Med Oncol 33:94

    Article  PubMed  CAS  Google Scholar 

  171. Silva EG, Tornos C, Bailey MA, Morris M (1991) Undifferentiated carcinoma of the ovary. Arch Pathol Lab Med 115:377–381

    CAS  PubMed  Google Scholar 

  172. Yang L, Zhang X, Ma Y, Zhao X, Li B, Wang H (2017) Ascites promotes cell migration through the repression of miR-125b in ovarian cancer. Oncotarget 8:51008–51015

    Article  PubMed  PubMed Central  Google Scholar 

  173. Pakula M, Mikula-Pietrasik J, Witucka A, Kostka-Jeziorny K, Uruski P, Moszynski R, Naumowicz E, Sajdak S, Tykarski A, Ksiazek K (2019) The epithelial-mesenchymal transition initiated by malignant ascites underlies the transmesothelial invasion of ovarian cancer cells. Int J Mol Sci 20:137

    Article  PubMed Central  CAS  Google Scholar 

  174. Carrel A (1912) On the permanent life of tissues outside of the organism. J Exp Med 15:516–528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Katakura Y, Nakata E, Miura T, Shirahata S (1999) Transforming growth factor beta triggers two independent-senescence programs in cancer cells. Biochem Biophys Res Commun 255:110–115

    Article  CAS  PubMed  Google Scholar 

  176. Cassar L, Nicholls C, Pinto AR, Chen R, Wang L, Li H, Liu JP (2017) TGF-beta receptor mediated telomerase inhibition, telomere shortening and breast cancer cell senescence. Protein Cell 8:39–54

    Article  CAS  PubMed  Google Scholar 

  177. Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-i S, Wada H, Fujimoto J, Kohno M (1999) Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 18:813–822

    Article  CAS  PubMed  Google Scholar 

  178. Kobayashi A, Okuda H, Xing F, Pandey PR, Watabe M, Hirota S, Pai SK, Liu W, Fukuda K, Chambers C, Wilber A, Watabe K (2011) Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J Exp Med 208:2641–2655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Reimann M, Lee S, Loddenkemper C, Dorr JR, Tabor V, Aichele P, Stein H, Dorken B, Jenuwein T, Schmitt CA (2010) Tumor stroma-derived TGF-beta limits myc-driven lymphomagenesis via Suv39h1-dependent senescence. Cancer Cell 17:262–272

    Article  CAS  PubMed  Google Scholar 

  180. Huynh ML, Fadok VA, Henson PM (2002) Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. J Clin Invest 109:41–50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Pakula M, Maly E, Uruski P, Witucka A, Bogucka M, Jaroszewska N, Makowska N, Niklas A, Moszynski R, Sajdak S, Tykarski A, Mikula-Pietrasik J, Ksiazek K (2020) Deciphering the molecular mechanism of spontaneous senescence in primary epithelial ovarian cancer cells. Cancers (Basel) 12:296

    Article  CAS  Google Scholar 

  182. Wang Z, Guo J, Zhou J, Liu H, Xu C (2019) Olaparib induced senescence under p16 or p53 dependent manner in ovarian cancer. J Gynecol Oncol 30:16

    Article  Google Scholar 

  183. Gao J, Zhu Y, Nilsson M, Sundfeldt K (2014) TGF-beta isoforms induce EMT independent migration of ovarian cancer cells. Cancer Cell Int 14:72

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. Ozturk N, Erdal E, Mumcuoglu M, Akcali KC, Yalcin O, Senturk S, rslan-Ergul A, Gur B, Yulug I, Cetin-Atalay R, Yakicier C, Yagci T, Tez M & Ozturk M, (2006) Reprogramming of replicative senescence in hepatocellular carcinoma-derived cells. Proc Natl Acad Sci USA 103:2178–2183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Verschueren K, Remacle JE, Collart C, Kraft H, Baker BS, Tylzanowski P, Nelles L, Wuytens G, Su MT, Bodmer R, Smith JC, Huylebroeck D (1999) SIP1, a novel zinc finger/homeodomain repressor, interacts with Smad proteins and binds to 5’-CACCT sequences in candidate target genes. J Biol Chem 274:20489–20498

    Article  CAS  PubMed  Google Scholar 

  186. Senturk S, Mumcuoglu M, Gursoy-Yuzugullu O, Cingoz B, Akcali KC, Ozturk M (2010) Transforming growth factor-beta induces senescence in hepatocellular carcinoma cells and inhibits tumor growth. Hepatology 52:966–974

    Article  CAS  PubMed  Google Scholar 

  187. Chaffer CL, Marjanovic ND, Lee T, Bell G, Kleer CG, Reinhardt F, D’Alessio AC, Young RA, Weinberg RA (2013) Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell 154:61–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Vermeulen L, De Sousa EMF, van der Heijden M, Cameron K, de Jong JH, Borovski T, Tuynman JB, Todaro M, Merz C, Rodermond H, Sprick MR, Kemper K, Richel DJ, Stassi G, Medema JP (2010) Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol 12:468–476

    Article  CAS  PubMed  Google Scholar 

  189. Kordon EC, McKnight RA, Jhappan C, Hennighausen L, Merlino G, Smith GH (1995) Ectopic TGF beta 1 expression in the secretory mammary epithelium induces early senescence of the epithelial stem cell population. Dev Biol 168:47–61

    Article  CAS  PubMed  Google Scholar 

  190. Tang B, Yoo N, Vu M, Mamura M, Nam JS, Ooshima A, Du Z, Desprez PY, Anver MR, Michalowska AM, Shih J, Parks WT, Wakefield LM (2007) Transforming growth factor-beta can suppress tumorigenesis through effects on the putative cancer stem or early progenitor cell and committed progeny in a breast cancer xenograft model. Cancer Res 67:8643–8652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Ehata S, Johansson E, Katayama R, Koike S, Watanabe A, Hoshino Y, Katsuno Y, Komuro A, Koinuma D, Kano MR, Yashiro M, Hirakawa K, Aburatani H, Fujita N, Miyazono K (2011) Transforming growth factor-beta decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells. Oncogene 30:1693–1705

    Article  CAS  PubMed  Google Scholar 

  192. Ciardiello D, Elez E, Tabernero J, Seoane J (2020) Clinical development of therapies targeting TGFbeta: current knowledge and future perspectives. Ann Oncol 31:1336–1349

    Article  CAS  PubMed  Google Scholar 

  193. Bogdahn U, Hau P, Stockhammer G, Venkataramana NK, Mahapatra AK, Suri A, Balasubramaniam A, Nair S, Oliushine V, Parfenov V, Poverennova I, Zaaroor M, Jachimczak P, Ludwig S, Schmaus S, Heinrichs H, Schlingensiepen KH, Trabedersen Glioma Study G (2011) Targeted therapy for high-grade glioma with the TGF-beta2 inhibitor trabedersen: results of a randomized and controlled phase IIb study. Neuro Oncol 13: 132–142.

  194. Formenti SC, Lee P, Adams S, Goldberg JD, Li X, Xie MW, Ratikan JA, Felix C, Hwang L, Faull KF, Sayre JW, Hurvitz S, Glaspy JA, Comin-Anduix B, Demaria S, Schaue D, McBride WH (2018) Focal irradiation and systemic TGFbeta blockade in metastatic breast cancer. Clin Cancer Res 24:2493–2504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Giaccone G, Bazhenova LA, Nemunaitis J, Tan M, Juhasz E, Ramlau R, van den Heuvel MM, Lal R, Kloecker GH, Eaton KD, Chu Q, Dunlop DJ, Jain M, Garon EB, Davis CS, Carrier E, Moses SC, Shawler DL, Fakhrai H (2015) A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer. Eur J Cancer 51:2321–2329

    Article  CAS  PubMed  Google Scholar 

  196. Melisi D, Garcia-Carbonero R, Macarulla T, Pezet D, Deplanque G, Fuchs M, Trojan J, Kozloff M, Simionato F, Cleverly A, Smith C, Wang S, Man M, Driscoll KE, Estrem ST, Lahn MMF, Benhadji KA, Tabernero J (2019) TGFbeta receptor inhibitor galunisertib is linked to inflammation- and remodeling-related proteins in patients with pancreatic cancer. Cancer Chemother Pharmacol 83:975–991

    Article  CAS  PubMed  Google Scholar 

  197. Yap TA, Vieito M, Baldini C, Sepulveda-Sanchez JM, Kondo S, Simonelli M, Cosman R, van der Westhuizen A, Atkinson V, Carpentier AF, Lohr M, Redman R, Mason W, Cervantes A, Le Rhun E, Ochsenreither S, Warren L, Zhao Y, Callies S, Estrem ST, Man M, Gandhi L, Avsar E, Melisi D (2021) First-in-human phase I Study of a next-generation, oral, TGFbeta receptor 1 inhibitor, LY3200882, in patients with advanced cancer. Clin Cancer Res 27:6666–6676

    Article  CAS  PubMed  Google Scholar 

  198. Paz-Ares L, Kim TM, Vicente D, Felip E, Lee DH, Lee KH, Lin CC, Flor MJ, Di Nicola M, Alvarez RM, Dussault I, Helwig C, Ojalvo LS, Gulley JL, Cho BC (2020) Bintrafusp Alfa, a bifunctional fusion protein targeting TGF-beta and PD-L1, in second-line treatment of patients with NSCLC: results from an expansion cohort of a phase 1 trial. J Thorac Oncol 15:1210–1222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Jung SY, Hwang S, Clarke JM, Bauer TM, Keedy VL, Lee H, Park N, Kim SJ, Lee JI (2020) Pharmacokinetic characteristics of vactosertib, a new activin receptor-like kinase 5 inhibitor, in patients with advanced solid tumors in a first-in-human phase 1 study. Invest New Drugs 38:812–820

    Article  CAS  PubMed  Google Scholar 

  200. Rocconi RP, Monk BJ, Walter A, Herzog TJ, Galanis E, Manning L, Bognar E, Wallraven G, Stanbery L, Aaron P, Senzer N, Coleman RL, Nemunaitis J (2021) Gemogenovatucel-T (Vigil) immunotherapy demonstrates clinical benefit in homologous recombination proficient (HRP) ovarian cancer. Gynecol Oncol 161:676–680

    Article  CAS  PubMed  Google Scholar 

  201. Ashrafizadeh M, Najafi M, Orouei S, Zabolian A, Saleki H, Azami N, Sharifi N, Hushmandi K, Zarrabi A, Ahn KS (2020) Resveratrol modulates transforming growth factor-beta (TGF-beta) signaling pathway for disease therapy: a new insight into its pharmacological activities. Biomedicines 8:261

    Article  CAS  PubMed Central  Google Scholar 

  202. Thacker PC, Karunagaran D (2015) Curcumin and emodin down-regulate TGF-beta signaling pathway in human cervical cancer cells. PLoS One 10:e0120045

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  203. Jhou BY, Song TY, Lee I, Hu ML, Yang NC (2017) Lycopene inhibits metastasis of human liver adenocarcinoma SK-Hep-1 cells by downregulation of NADPH oxidase 4 protein expression. J Agric Food Chem 65:6893–6903

    Article  CAS  PubMed  Google Scholar 

  204. Giacomelli C, Daniele S, Natali L, Iofrida C, Flamini G, Braca A, Trincavelli ML, Martini C (2017) Carnosol controls the human glioblastoma stemness features through the epithelial-mesenchymal transition modulation and the induction of cancer stem cell apoptosis. Sci Rep 7:15174

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  205. Boldbaatar A, Lee S, Han S, Jeong AL, Ka HI, Buyanravjikh S, Lee JH, Lim JS, Lee MS, Yang Y (2017) Eupatolide inhibits the TGF-beta1-induced migration of breast cancer cells via downregulation of SMAD3 phosphorylation and transcriptional repression of ALK5. Oncol Lett 14:6031–6039

    PubMed  PubMed Central  Google Scholar 

  206. Avila-Carrasco L, Majano P, Sanchez-Tomero JA, Selgas R, Lopez-Cabrera M, Aguilera A, Gonzalez Mateo G (2019) Natural plants compounds as modulators of epithelial-to-mesenchymal transition. Front Pharmacol 10:715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The authors of the study are supported by a grant from the National Science Centre, Poland (registration number 2020/37/B/NZ5/00100).

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed to the study conception, design, and writing.

Corresponding author

Correspondence to Krzysztof Książek.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mikuła-Pietrasik, J., Rutecki, S. & Książek, K. The functional multipotency of transforming growth factor β signaling at the intersection of senescence and cancer. Cell. Mol. Life Sci. 79, 196 (2022). https://doi.org/10.1007/s00018-022-04236-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00018-022-04236-y

Keywords

Navigation