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Original Research

Open Access Special Issue

Association of cancer-associated fibroblasts and survival in malignant ovarian neoplasms

  • Ana Carolinne da Silva1
  • Millena Prata Jammal1
  • Renata Margarida Etchebehere2
  • Eddie Fernando Candido Murta1
  • Rosekeila Simões Nomelini1,*,

1Department of Gynecology and Obstetrics/Research Institute of Oncology (IPON), Federal University of Triângulo Mineiro, 38025-440 Uberaba-MG, Brazil

2Surgical Pathology Service, Federal University of Triângulo Mineiro, 38025-440 Uberaba-MG, Brazil

DOI: 10.31083/j.ejgo4204118 Vol.42,Issue 4,August 2021 pp.782-787

Submitted: 18 April 2021 Accepted: 21 June 2021

Published: 15 August 2021

(This article belongs to the Special Issue Immunology in Gynecological Cancer)

*Corresponding Author(s): Rosekeila Simões Nomelini E-mail: rosekeila@terra.com.br; rosekeila.nomelini@pesquisador.cnpq.br

Abstract

Objective: The aims of the study were to compare the stromal immunostaining of smooth muscle alpha-actin (α-SMA) and fibroblast activation protein-α (FAP) between borderline ovarian tumors and epithelial ovarian cancer, and to evaluate their association in overall survival (OS) and disease-free survival (DFS) in patients with ovarian cancer. Methods: Patients diagnosed with malignant (n = 28) and borderline ovarian tumors (n = 18) were evaluated. Immunohistochemical study of stromal α-SMA and FAP was carried out. The comparison of immunostaining between borderline and malignant ovarian tumors was performed using Fisher’s exact test. Survival was assessed by the Kaplan-Meier method and the log-rank test. Multivariate analysis was performed by Cox regression. The differences were considered significant for p < 0.05. Results: Evaluating stromal FAP, stronger immunostaining (2 and 3) was more often found in epithelial ovarian cancer than in borderline ovarian tumors (p = 0.0331). There was no statistical significance in the assessment of α-SMA. Evaluating only patients with epithelial ovarian cancer, there was a higher OS in patients with stromal α-SMA immunostaining 3 (p = 0.017). There was no statistical significance when evaluating OS and DFS in patients with stromal FAP immunostaining, nor evaluating DFS in patients with α-SMA stromal immunostaining 3. After multivariate analysis, patients with stromal α-SMA immunostaining 3 had higher OS compared to immunostaining 0, 1 or 2 [OR (95% CI) = 0.107 (0.018–0.649), p = 0.015]. Conclusion: Stronger FAP immunostaining was more often found in epithelial ovarian cancer than in borderline ovarian tumors. In epithelial ovarian cancer, there was a higher OS in patients with stromal α-SMA immunostaining 3.


Keywords

Epithelial ovarian cancer; Borderline ovarian tumors; Smooth muscle alpha-actin; Fibroblast activation protein-α; Tumor microenvironment; Overall sur-vival

Cite and Share

Ana Carolinne da Silva,Millena Prata Jammal,Renata Margarida Etchebehere,Eddie Fernando Candido Murta,Rosekeila Simões Nomelini. Association of cancer-associated fibroblasts and survival in malignant ovarian neoplasms. European Journal of Gynaecological Oncology. 2021. 42(4);782-787.

References

[1] Berkenblit A, Cannistra SA. Advances in the management of epithelial ovarian cancer. Journal of Reproductive Medicine. 2005; 50: 426–438.

[2] Coburn SB, Bray F, Sherman ME, Trabert B. International patterns and trends in ovarian cancer incidence, overall and by histologic subtype. International Journal of Cancer. 2017; 140: 2451–2460.

[3] Polgár L. The prolyl oligopeptidase family. Cellular and Molecular Life Sciences. 2002; 59: 349–362.

[4] Mhawech-Fauceglia P, Yan L, Sharifian M, Ren X, Liu S, Kim G, et al. Stromal Expression of Fibroblast Activation Protein Alpha (FAP) Predicts Platinum Resistance and Shorter Recurrence in patients with Epithelial Ovarian Cancer. Cancer Microenvironment. 2015; 8: 23–31.

[5] Kelly T, Huang Y, Simms AE, Mazur A. Fibroblast Activation Protein-α: a key modulator of the microenvironment in multiple pathologies. International Review of Cell and Molecular Biology. 2012; 40: 83–116.

[6] Scanlan MJ, Raj BK, Calvo B, Garin-Chesa P, Sanz-Moncasi MP, Healey JH, et al. Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Proceedings of the National Academy of Sciences of the United States of America. 1994; 91: 5657–5661.

[7] Bae S, Park CW, Son HK, Ju HK, Paik D, Jeon C, et al. Fibroblast activation protein alpha identifies mesenchymal stromal cells from human bone marrow. British Journal of Haematology. 2008; 142: 827–830.

[8] Cohen SJ, Alpaugh RK, Palazzo I, Meropol NJ, Rogatko A, Xu Z, et al. Fibroblast activation protein and its relationship to clinical outcome in pancreatic adenocarcinoma. Pancreas. 2008; 37: 154–158.

[9] Shi M, Yu D, Chen Y, Zhao C, Zhang J, Liu Q, et al. Expression of fibroblast activation protein in human pancreatic adenocarcinoma and its clinicopathological significance. World Journal of Gastroenterology. 2012; 18: 840–846.

[10] Henry LR, Lee H, Lee JS, Klein-Szanto A, Watts P, Ross EA, et al. Clinical implications of fibroblast activation protein in patients with colon cancer. Clinical Cancer Research. 2007; 13: 1736–1741.

[11] Zhang Y, Tang H, Cai J, Zhang T, Guo J, Feng D, et al. Ovarian cancer-associated fibroblasts contribute to epithelial ovarian carcinoma metastasis by promoting angiogenesis, lymphangiogenesis and tumor cell invasion. Cancer Letters. 2011; 303: 47–55.

[12] Weymouth N, Shi Z, Rockey DC. Smooth muscle α actin is specifically required for the maintenance of lactation. Developmental Biology. 2012; 363: 1–14.

[13] Vandekerckhove J, Weber K. At least six different actins are expressed in a higher mammal: an analysis based on the amino acid sequence of the amino-terminal tryptic peptide. Journal of Molecular Biology. 1978; 126: 783–802.

[14] Sun K, Chang Y, Reed NI, Sheppard D. Α-Smooth muscle actin is an inconsistent marker of fibroblasts responsible for force-dependent TGFβ activation or collagen production across multiple models of organ fibrosis. American Journal of Physiology. Lung Cellular and Molecular Physiology. 2016; 310: L824–L836.

[15] Anggorowati N, Ratna Kurniasari Ch, Damayanti K, Cahyanti T, Widodo I, Ghozali A, et al. Histochemical and Immunohistochemical Study of α-SMA, Collagen, and PCNA in Epithelial Ovarian Neoplasm. Asian Pacific journal of cancer prevention. 2017; 18: 667–671.

[16] Cherng S, Young J, Ma H. Alpha-smooth muscle actin (α-SMA). Journal of American Science. 2008; 4: 7–9

[17] Shinde AV, Humeres C, Frangogiannis NG. The role of α-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling. Biochimica Et Biophysica Acta. Molecular Basis of Disease. 2017; 1863: 298–309.

[18] da Silva A, Jammal M, Etchebehere R, Murta E, Nomelini R. Role of Alpha-Smooth Muscle Actin and Fibroblast Activation Protein Alpha in Ovarian Neoplasms. Gynecologic and Obstetric Investigation. 2018; 83: 381–387.

[19] Shiga K, Hara M, Nagasaki T, Sato T, Takahashi H, Takeyama H. Cancer-Associated Fibroblasts: their Characteristics and their Roles in Tumor Growth. Cancers. 2015; 7: 2443–2458.

[20] Zeppernick F, Meinhold-Heerlein I. The new FIGO staging system for ovarian, fallopian tube, and primary peritoneal cancer. Archives of Gynecology and Obstetrics. 2014; 290: 839–842.

[21] Zhang X, Hwang YS. Cancer-associated fibroblast stimulates cancer cell invasion in an interleukin-1 receptor (IL-1R)-dependent manner. Oncology Letters. 2019; 18: 4645–4650.

[22] Hinshaw DC, Shevde LA. The Tumor Microenvironment Innately Modulates Cancer Progression. Cancer Research. 2019; 79: 4557–4566.

[23] Hamson EJ, Keane FM, Tholen S, Schilling O, Gorrell MD. Understanding fibroblast activation protein (FAP): Substrates, activities, expression and targeting for cancer therapy. Clinical Applications. 2014; 8: 454–463.

[24] Ebert LM, Yu W, Gargett T, Toubia J, Kollis PM, Tea MN, et al. Endothelial, pericyte and tumor cell expression in glioblastoma identifies fibroblast activation protein (FAP) as an excellent target for immunotherapy. Clinical & Translational Immunology. 2020; 9: e1191.

[25] Ostermann E, Garin-Chesa P, Heider KH, Kalat M, Lamche H, Puri C, et al. Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts. Clinical Cancer Research. 2008; 14: 4584–4592.

[26] Kakarla S, Chow KKH, Mata M, Shaffer DR, Song X, Wu M, et al. Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma. Molecular Therapy. 2013; 21: 1611–1620.

[27] Gulati P, Rühl J, Kannan A, Pircher M, Schuberth P, Nytko KJ, et al. Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice. Clinical Cancer Research. 2018; 24: 3981–3993.

[28] Freedman JD, Duffy MR, Lei-Rossmann J, Muntzer A, Scott EM, Hagel J, et al. An Oncolytic Virus Expressing a T-cell Engager Simultaneously Targets Cancer and Immunosuppressive Stromal Cells. Cancer Research. 2018; 78: 6852–6865.

[29] Schuberth PC, Hagedorn C, Jensen SM, Gulati P, van den Broek M, Mischo A, et al. Treatment of malignant pleural mesothelioma by fibroblast activation protein-specific redirected T cells. Journal of Translational Medicine. 2013; 11: 187.

[30] Zhang M, Xu L, Wang X, Sun B, Ding J. Expression levels of seprase/FAPα and DPPIV/CD26 in epithelial ovarian carcinoma. Oncology Letters. 2015; 10: 34–42.

[31] Nurmik M, Ullmann P, Rodriguez F, Haan S, Letellier E. In search of definitions: Cancer‐associated fibroblasts and their markers. International Journal of Cancer. 2020; 146: 895–905.

[32] Micallef L, Vedrenne N, Billet F, Coulomb B, Darby IA, Desmoulière A. The myofibroblast, multiple origins for major roles in normal and pathological tissue repair. Fibrogenesis & Tissue Repair. 2012; 5: S5.

[33] Mezawa Y, Orimo A. The roles of tumor- and metastasis-promoting carcinoma-associated fibroblasts in human carcinomas. Cell and Tissue Research. 2016; 365: 675–689.

[34] Gascard P, Tlsty TD. Carcinoma-associated fibroblasts: orches-trating the composition of malignancy. Genes & Development. 2016; 30: 1002–1019.

[35] Surowiak P, Murawa D, Materna V, Maciejczyk A, Pudelko M, Ciesla S, et al. Occurence of stromal myofibroblasts in the invasive ductal breast cancer tissue is an unfavourable prognostic factor. Anticancer Research. 2007; 27: 2917–2924.

[36] Tsujino T, Seshimo I, Yamamoto H, Ngan CY, Ezumi K, Takemasa I, et al. Stromal myofibroblasts predict disease recurrence for colorectal cancer. Clinical Cancer Research. 2007; 13: 2082–2090.

[37] Sinn M, Denkert C, Striefler JK, Pelzer U, Stieler JM, Bahra M, et al. α-Smooth muscle actin expression and desmoplastic stromal reaction in pancreatic cancer: results from the CONKO-001 study. Clinical Cancer Research. 2014; 111: 1917–1923.

[38] Franco OE, Shaw AK, Strand DW, Hayward SW. Cancer associated fibroblasts in cancer pathogenesis. Seminars in Cell & Developmental Biology. 2010; 21: 33–39.

[39] Kalluri R, Zeisberg M. Fibroblasts in cancer. Nature Reviews. Cancer. 2006; 6: 392–401.

[40] Östman A, Augsten M. Cancer-associated fibroblasts and tumor growth – bystanders turning into key players. Current Opinion in Genetics & Development. 2009; 19: 67–73.

[41] Spaeth EL, Dembinski JL, Sasser AK, Watson K, Klopp A, Hall B, et al. Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS ONE. 2009; 4: e4992.

[42] Ge Y, Zhan F, Barlogie B, Epstein J, Shaughnessy J, Yaccoby S. Fibroblast activation protein (FAP) is upregulated in myelomatous bone and supports myeloma cell survival. British Journal of Haematology. 2006; 133: 83–92.

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