Stromal Expression of Fibroblast Activation Protein Alpha (FAP) Predicts Platinum Resistance and Shorter Recurrence in patients with Epithelial Ovarian Cancer

Paulette Mhawech-Fauceglia, Li Yan, Maryam Sharifian, Xing Ren, Song Liu, Grace Kim, Simon A. Gayther, Tanja Pejovic, Kate Lawrenson

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The microenvironment plays an important role in tumorigenesis. Fibroblast activation protein alpha (FAP) is overexpressed by fibroblasts present in the microenvironment of many tumors. High FAP expression is a negative prognostic factor in several malignancies, but this has not been investigated in epithelial ovarian cancer (EOC). The aim of this study is to define the value of FAP in EOC. Immunohistochemical staining using an anti-FAP antibody was performed on 338 EOC tissues. mRNA levels in cancer cell lines and FAP silencing using siRNA was also done. FAP immunoexpression by tumor stroma was a significant predictive factor for platinum resistance (p = 0.0154). In survival analysis of days to recurrence, FAP stoma+ was associated with shorter recurrence than those with FAP stroma (p = 0.0247). In 21.8 % of tumors, FAP protein was expressed by the tumor epithelium, and FAP mRNA was more highly expressed in tumors (n = 489) than in normal tissues (n = 8) (p = 3.88 × 10−4). In vitro, addition of FAP to EOC cells induced a 10–12 % increase in cell viability both in the presence and absence of cisplatin. Conversely, siRNA silencing of FAP resulted in ~10 % reduction in EOC cell proliferation. We have shown that FAP expression in EOC is associated with poorer clinical outcomes. FAP may have novel cell-autonomous effects suggesting that targeting FAP could have pleiotropic anti-tumor effects, and anti-FAP therapy could be a highly effective novel treatment for EOC, especially in cisplatinum-resistant cases.

Original languageEnglish (US)
Pages (from-to)23-31
Number of pages9
JournalCancer Microenvironment
Volume8
Issue number1
DOIs
StatePublished - Oct 21 2014

Fingerprint

Platinum
Recurrence
Neoplasms
fibroblast activation protein alpha
Ovarian epithelial cancer
Small Interfering RNA
Messenger RNA
Tumor Microenvironment
R Factors
Survival Analysis
Cisplatin
Cell Survival
Carcinogenesis

Keywords

  • Cancer-associated fibroblast
  • Disease outcome
  • Epithelial ovarian cancer
  • Fibroblast activation protein
  • Platinum resistance
  • Tumor microenvironment

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Stromal Expression of Fibroblast Activation Protein Alpha (FAP) Predicts Platinum Resistance and Shorter Recurrence in patients with Epithelial Ovarian Cancer. / Mhawech-Fauceglia, Paulette; Yan, Li; Sharifian, Maryam; Ren, Xing; Liu, Song; Kim, Grace; Gayther, Simon A.; Pejovic, Tanja; Lawrenson, Kate.

In: Cancer Microenvironment, Vol. 8, No. 1, 21.10.2014, p. 23-31.

Research output: Contribution to journalArticle

Mhawech-Fauceglia, Paulette ; Yan, Li ; Sharifian, Maryam ; Ren, Xing ; Liu, Song ; Kim, Grace ; Gayther, Simon A. ; Pejovic, Tanja ; Lawrenson, Kate. / Stromal Expression of Fibroblast Activation Protein Alpha (FAP) Predicts Platinum Resistance and Shorter Recurrence in patients with Epithelial Ovarian Cancer. In: Cancer Microenvironment. 2014 ; Vol. 8, No. 1. pp. 23-31.
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AU - Yan, Li

AU - Sharifian, Maryam

AU - Ren, Xing

AU - Liu, Song

AU - Kim, Grace

AU - Gayther, Simon A.

AU - Pejovic, Tanja

AU - Lawrenson, Kate

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AB - The microenvironment plays an important role in tumorigenesis. Fibroblast activation protein alpha (FAP) is overexpressed by fibroblasts present in the microenvironment of many tumors. High FAP expression is a negative prognostic factor in several malignancies, but this has not been investigated in epithelial ovarian cancer (EOC). The aim of this study is to define the value of FAP in EOC. Immunohistochemical staining using an anti-FAP antibody was performed on 338 EOC tissues. mRNA levels in cancer cell lines and FAP silencing using siRNA was also done. FAP immunoexpression by tumor stroma was a significant predictive factor for platinum resistance (p = 0.0154). In survival analysis of days to recurrence, FAP stoma+ was associated with shorter recurrence than those with FAP− stroma (p = 0.0247). In 21.8 % of tumors, FAP protein was expressed by the tumor epithelium, and FAP mRNA was more highly expressed in tumors (n = 489) than in normal tissues (n = 8) (p = 3.88 × 10−4). In vitro, addition of FAP to EOC cells induced a 10–12 % increase in cell viability both in the presence and absence of cisplatin. Conversely, siRNA silencing of FAP resulted in ~10 % reduction in EOC cell proliferation. We have shown that FAP expression in EOC is associated with poorer clinical outcomes. FAP may have novel cell-autonomous effects suggesting that targeting FAP could have pleiotropic anti-tumor effects, and anti-FAP therapy could be a highly effective novel treatment for EOC, especially in cisplatinum-resistant cases.

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