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. 2015 Dec 29;6(42):44551-62.
doi: 10.18632/oncotarget.6082.

Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer (V体育ios版)

Kim Moran-Jones  1   2 , Brian S Gloss  1   2 , Rajmohan Murali  3 , David K Chang  1 , Emily K Colvin  4 , Marc D Jones  1 , Samuel Yuen  4 , Viive M Howell  4 , Laura M Brown  1 , Carol W Wong  5 , Suzanne M Spong  5 , Christopher J Scarlett  1   6 , Neville F Hacker  7 , Sue Ghosh  8 , Samuel C Mok  9 , Michael J Birrer  10 , Goli Samimi  1   2
Affiliations

Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer

Kim Moran-Jones et al. Oncotarget. .

Abstract

Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer. VSports手机版.

Keywords: CTGF; FG-3019; metastasis; ovarian cancer; tumor microenvironment. V体育安卓版.

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Conflict of interest statement

CONFLICTS OF INTEREST

KM-J, BG, RM, DKC, EKC, MDJ, SY, VMH, LMB, CJS, NFH, SG, SCM, MJB and GS declare no conflict of interest. CWW and SMS are employed by FibroGen Inc V体育ios版.

"V体育ios版" Figures

Figure 1
Figure 1. Unsupervised hierarchical clustering dendogram of microdissected fibroblasts from 51 HGSOC tumors and 10 normal ovarian tissues, using 9,741 probe sets that passed filtering criteria
Figure 2
Figure 2. Immunohistochemical staining of CTGF on formalin-fixed tissue sections
A. Normal ovary (inset shows higher magnification of boxed region). Arrows indicate an absence of CTGF expression in normal ovarian surface epithelium. B. HGSOC with high-levels of stromal CTGF expression. C. A negative control using normal rabbit IgG on a HGSOC with high-levels of stromal CTGF expression. S = stroma, T = tumor. Bar = 50 μm. D. Correlation between CTGF stromal expression by real-time PCR and by immunohistochemistry in 17 HGSOC tumors (Pearson's r = 0.636). E. CTGF expression in HGSOC stroma as measured by microarray in our study, and studies described by Tothill et al. [15] and Lili et al. [16]. *p-value < 10−5, **p-value < 0.02.
Figure 3
Figure 3. Functional studies of CTGF and FG-3019
A. Migration of A224, OVCAR3 and SKOV3 cells in response to increasing concentrations of rhCTGF. B. 6-hour migration of A224, OVCAR3 and SKOV3 cells (untreated); with 5 μg/ml CTGF; with 5 μg/ml CTGF+100 μg/ml FG-3019 and with 5 μg/ml CTGF+100 μg/ml IgG. Each bar represents the mean of triplicate wells ± SD. Ex vivo peritoneal tissue adhesion of OVCAR3 cells C. and SKOV3 cells D. Untreated; with 5 μg/ml rhCTGF (CTGF) with 5 μg/ml rhCTGF+50 μg/ml FG-3019; with 5 μg/ml rhCTGF+50 μg/ml IgG and with 50 μg/ml FG-3019. Each bar represents the average adhesion in at least 2 wells in 2 independent experiments ± SD. E. Ex vivo peritoneal tissue adhesion of OVCAR3 and SKOV3 cells: untreated; with 5 μg/ml rhCTGF; and with 5 μg/ml rhCTGF/20 μg/ml anti-α5β1 antibody. Each bar represents the average adhesion in at least 2 wells in 2 independent experiments ± SD. *p-value < 0.05, **p-value < 0.01, ***p-value < 0.005.
Figure 4
Figure 4. Representative examples of immunohistochemical staining of CTGF by FG-3145 in stromal fibroblasts of formalin-fixed HGSOC tissues
A. Normal ovary; no CTGF expression B. tumor; no CTGF expression C. tumor; intensity = 1, percentage = 30% D. tumor; intensity = 2, percentage = 70% E. tumor; intensity = 3, percentage = 95%. Bar = 100 μm.
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