Abstract
The growth factors derived from the microenvironment create an environment conducive to tumor growth and survival. HGF deprivation using neutralizing antibody enhanced chemosensitivity in colorectal cancer cells (CRC). We determined secreted HGF in fibroblast conditioned medium (CM). Combination treatment of anti-HGF antibody and irinotecan (CPT-11) directly enhanced CPT-11 sensitivity in CRC. We generated xenograft in NOD/SCID mice inoculating HCT-116 human colorectal cancer cells subcutaneously with or without fibroblast. We found that the combination of CPT-11 and anti-HGF antibody induced marked suppression of tumor development. These results suggest that HGF produced by fibroblast induce CPT-11 resistance, and that anti-HGF antibody abrogate such resistance in vivo. fibroblast-derived HGF is important determinant of chemoresistance. Anti-HGF monoclonal antibody treatment confirmed the importance of this growth factor for chemoresistance in CRC. These results present new options toward the early diagnosis of chemoresistance and suggest novel combinations of chemotherapy and anti-HGF agents to prevent or significantly delay the onset of therapy resistance.
Highlights
Hepatocyte growth factor (HGF), known as scatter factor, is a pleiotropic polypeptide growth factor with a number of biological activities, including cell scattering, stimulation of cell motility, mitogenesis, morphogenesis, angiogenesis, and cellular invasiveness [13]
To determine if the rescue effect was activated by the secretion factors, we tested the ability of conditioned medium (CM) from fibroblasts to recapitulate the resistance effect
Our findings suggest that the fibroblast-derived HGF may play an important role in cancer cell survival and that the interference with its effect in tumor cells may represent a novel strategy for the treatment of colorectal cancers
Summary
Hepatocyte growth factor (HGF), known as scatter factor, is a pleiotropic polypeptide growth factor with a number of biological activities, including cell scattering, stimulation of cell motility, mitogenesis, morphogenesis, angiogenesis, and cellular invasiveness [13]. HGF and its receptor, the c-MET proto-oncogene product, are thought to be involved in embryogenesis, tissue reorganization, and tumor progression [8]. Overproduction of HGF by tumor cells or tumor-associated stromal cells and increased expression of the c-Met protein are two mechanisms that contribute to aberrant stimulation of this pathway. Consequences of dysregulated HGF and c-Met expression include tumor cell migration, proliferation, and protection from apoptosis [9]. Overexpression of HGF and c-Met has been detected in numerous cancer types and is associated with a worse prognosis [10]
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