Tumor-stroma interactions in
hepatocellular carcinoma (HCC) are of key importance to
tumor progression. In this study, we show that HCC invasive cells produce high levels of
connective tissue growth factor (CTGF) and generate
tumors with a high stromal component in a xenograft model. A
transforming growth factor beta (
TGF-beta) receptor inhibitor,
LY2109761, inhibited the synthesis and release of CTGF, as well as reducing the stromal component of the
tumors. In addition, the
TGF-beta-dependent down-regulation of CTGF diminished
tumor growth, intravasation, and metastatic dissemination of HCC cells by inhibiting cancer-associated fibroblast proliferation. By contrast, noninvasive HCC cells were found to produce low levels of CTGF. Upon
TGF-beta1 stimulation, noninvasive HCC cells form
tumors with a high stromal content and CTGF expression, which is inhibited by treatment with
LY2109761. In addition, the acquired intravasation and metastatic spread of noninvasive HCC cells after
TGF-beta1 stimulation was blocked by
LY2109761.
LY2109761 interrupts the cross-talk between
cancer cells and cancer-associated fibroblasts, leading to a significant reduction of HCC growth and dissemination. Interestingly, patients with high CTGF expression had poor prognosis, suggesting that treatment aimed at reducing
TGF-beta-dependent CTGF expression may offer clinical benefits.
CONCLUSION: Taken together, our preclinical results indicate that
LY2109761 targets the cross-talk between HCC and the stroma and provide a rationale for future clinical trials.