Down-regulation of connective tissue growth factor by inhibition of transforming growth factor β blocks the tumor-stroma cross-talk and tumor progression in hepatocellular carcinoma

Abstract

D rug-based treatments to cure patients with hepatocellular carcinoma (HCC) remain a highly desirable goal in drug development because socalled curative therapies are successful in only few patients. 1 The approval of sorafenib for the treatment of patients with advanced-stage disease has stimulated the investigation of new therapeutic strategies. 2 However, the development of new drugs is hampered by the heterogeneity of HCC and the underlying liver disease type, which limit the recognition of useful therapeutic targets. 3 Because HCC generally develops in fibrotic tissue, the growth of tumor cells is dependent on an intricate crosstalk between the tumor and the stroma. Due to this complexity and interaction with fibrotic liver, HCC cells develop a cross-talk with adjacent components of the tissue microenvironment, including extracellular matrix proteins and various growth factors. A growing body of evidence suggests that the cross-talk affects the malignant phenotype and is a key factor of poor clinical outcome. Cancer-associated fibroblasts (CAFs), a heterogeneous population of stromal cells, play a central role in this stroma-tumor interaction, involving the production of growth factors, which in turn may reduce the effect of chemotherapy and radiotherapy. 4,5 CAFs can form after stimulation with transforming growth factor ␤-1 (TGF-␤1), which plays an important role in HCC by stimulat-

The transcriptional coactivators megakaryoblastic leukemia 1/2 mediate the effects of loss of the tumor suppressor deleted in liver cancer 1

“…Activation of CTGF expression was due to DLC1 loss, because rescue of DLC1 suppressed CTGF expression. Hepatocellular and breast cancers contain high levels of CTGF, which has been shown to have a role in tumor progression (Xie et al, 2001;Mazzocca et al, 2010).…”

“…Two immediate early genes known to be SRF target genes (Selvaraj and Prywes, 2004;Miano et al, 2007;Muehlich et al, 2007), namely connective tissue growth factor (CTGF) and integrin alpha 5 (Itga5), showed preferential expression in HuH7 versus HepG2 cells, as well as MDA-MB-468 versus MCF7 cells (Figure 5b and Supplementary Figure S4). Both have been reported to have an important role in tumorigenesis (Friedl and Wolf, 2003;Mazzocca et al, 2010). However, MKL dependence has not been determined yet.…”

Transforming Growth Factor-β as a Therapeutic Target in Hepatocellular Carcinoma

“…TGF-b signaling is associated with loss of cell polarity, acquisition of cellular motility, and increased tumor invasion (5,(16)(17)(18)(19)(20)(21)(22). A main change in tumor cells is related to EMT as measured by E-cadherin expression, a marker of EMT.…”

“…LY2157299 seems to also block the CTGF production with the consequent reduction of stromal reaction. This reduces tumor growth in experimental models and will likely have a beneficial impact on the cirrhotic process (17,20). LY2157299 also reduces hepatocellular carcinoma growth and progression by inhibiting neoangiogenesis.…”

Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets

“…Cancer cells are not as autonomous as once thought, they depend on angiogenesis, inflammatory cells and fibroblasts [77,78] . Obvious, in the cirrhotic liver there is an abundancy of fibroblasts and there is emerging evidence that some are cancer associated fibroblasts (CAFs) [79] . In HCC, the progression of malignant hepatocytes frequently depends on transforming growth factor (TGF)-beta provided by the stromal cells (fibroblasts, macrophages etc).…”