Targeting transforming growth factor-b signaling in liver metastasis

Targeting transforming growth factor-b signaling in liver metastasis of colon cancer

Bixiang Zhang^a, Sunil K. Halder^a, Sanguo Zhang^a and Pran K. Datta^{, a,}

^aDepartments of Surgery and Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 1161 21st Avenue South, A-3310C, MCN, Nashville, TN 37232, USA

Summary:

Transforming Growth Factor-Beta (TGF-β) is a multifunctional peptide that controls proliferation, differentiation and other functions in many cell types. There is compelling evidence suggesting that TGF-β can promote tumor growth, invasion and metastasis in advanced stages of colorectal cancer. However, little is known about how the inhibitors of TGF-β receptor kinases affect colorectal carcinogenesis.

For that reason this study used CT26 cells that were derived from an undifferentiated murine adenocarcinoma and extracted their genomic DNA. Then they ran PCR using the extracted DNA to examine mutations in specific codons. Then CT26 cells were treated with either TGF-β, LY2109761 (TGF-β receptor), or a combination of TGF-β1 and LY2109761. For immunoprecipitation assays, lysates prepared from TGF-β1 treated CT26 cells were incubated with appropriate antibodies. Immune complexes were precipitated, washed, and analyzed by western blotting.

After a series of cell counting assay, running ELISA for TGF-β1, cell migration and cell invasion assays and wound healing assays they found that CT26 cells contain LY2109761 inhibits TGF-β-mediated signaling. Also that LY2109761 inhibits TGF-β-induced cell migration. Results also showed that invasion of TGF-β had no significant effect on the growth of CT26 cells. All of these findings ultimately mean LY2109761 treatment reduces colon cancer liver metastasis and prolongs the survival of metastatic tumor-bearing cells. The results also indicate that TGF-β plays an important role in cancer progression and increased production of TGF-β in human tumors is correlated with poor prognosis.

Furthermore, LY2109761 decreases liver metastases and prolongs survival in an experimental metastasis model. These findings suggest that the inhibitor LY2109761 has potential therapeutic value for metastatic colorectal cancer.

Significance:

Blocking tumor-promoting effects of growth factors provides a potentially important therapeutic strategy for the treatment of different types of cancer. In this case most human cancers, cells first become resistant to TGF-β-induced growth inhibition and apoptosis. In the later stages of cancer progression, high levels of TGF-β can promote tumorigenicity in an autocrine and/or paracrine manner by promoting invasion and metastasis. Therefore, the rational design of inhibitors that specifically counteract the tumor-promoting effects of TGF-β may be useful as a therapeutic strategy for the treatment of human cancers.