Hepatocyte growth factor and the Met system as a mediator of tumor–stromal interactions

Abstract

Crosstalk between carcinoma cells and host stromal cells such as fibroblasts has a great deal of influence on the invasive and metastatic behavior of cancer cells. The oncogenic action of fibroblasts has been demonstrated through genetic alterations that occur specifically in fibroblasts. Hepatocyte growth factor (HGF), a ligand for the Met receptor tyrosine kinase, plays a definitive role, particularly in the progression to invasive and metastatic cancers, predominantly as a stroma-derived paracrine mediator. Many types of cancer cells secrete molecules that enhance HGF production in fibroblasts, while fibroblast-derived HGF, in turn, is a potent stimulator of the invasion of cancer cells. Fibroblast-specific genetic alterations leading to an overexpression of HGF are associated with the development of epithelial neoplasia and invasive carcinoma. Strategies for targeting the HGF-Met axis are being pursued, in attempts to block the malignant behavior of cancers. In normal tissues, the HGF-Met axis plays diverse roles in organogenesis and in wound healing. The simile that ''cancer is a never-healing wound'' appears to be pertinent here. ' 2006 Wiley-Liss, Inc.

Origin of carcinoma associated fibroblasts

“…We consider the CAFs as part of these cancer microenvironment changes that occur in tissue lesions and serve as precursors for malignant disease. Several hypotheses have been presented for the origin of these altered cells, including standard connective tissue acute phase and stress response, 55,80,81 and fibroblast senescence, [82][83][84][85] reciprocal interactions with the cancer cells, 5,20,[86][87][88][89][90] fibroblast specific somatic mutations, [91][92][93][94][95] differentiation precursors and infiltrating mesenchymal stem cell. 96,97 …”

Inhibitory effect of HGF on invasiveness of aggressive MDA-MB231 breast carcinoma cells, and role of HDACs

“…The site of metastasis depends on the characteristics of neoplastic cells and of the permissive microenvironment in the metastatic target organ for incoming cancer cells (Yilmaz et al, 2007). Chemokines and growth factors, such as HGF, seem to act as mediators between the tumour microenvironment and the neoplastic cells, and are important in tumour progression and metastasis (Matsumoto and Nakamura, 2006;Benvenuti and Comoglio, 2007;Desiderio, 2007;Singh et al, 2007). Second, we examined the mechanistic basis of the differences in breast tumour cell responses to TSA, depending on tumour aggressiveness, and considered the transcriptional regulation of CXCR4 and Met, two genes important for tumour cell invasiveness (Benvenuti and Comoglio, 2007;Furlan et al, 2008).…”

“…Hepatocyte growth factor (HGF) is a multifunctional cytokine produced by cells of the supportive tumour microenvironment, and a central regulator of the invasive/metastatic phenotype of neoplastic cells (Matsumoto and Nakamura, 2006;Mazzone and Comoglio, 2006;Desiderio, 2007). Through Met receptor binding, HGF aberrantly activates the motility/chemoinvasion, proliferation/survival and apoptosis that characterize the epithelial-mesenchymal transition of aggressive carcinomas.…”

“…Trichostatin A only partly counteracted HGF-inhibitory effect on chemoinvasion because it enhanced CXCR4 expression by ETS1 activation/c-Src activity reduction, but triggered apoptosis through inhibition of the Akt/NF-kB pathway. The diminished CXCR4 function at the secondary growth site, where HGF seems to be produced (Matsumoto and Nakamura, 2006;Benvenuti and Comoglio, 2007), probably has biological implications: the homing of metastatic cells such as MDA-MB231, attracted by CXCL12, might be enhanced if HGF reduced their motility.…”

Senescence, Wound Healing, and Cancer: the PAI-1 Connection

“…[24][25][26] Over the past years these links have been substantiated by showing that molecules involved in inflammation and wound healing are causally involved in cancer. 25,[27][28][29][30][31] Fibroblasts play a causal role in wound healing, which in the initial phase is driven by heterotypic signaling between fibroblasts and immune system cells recruited during inflammation, such as platelets, macrophages, leukocytes and mast cells. 32,33 During cutaneous wound healing, following activation by inflammatory molecules, fibroblasts proliferate and migrate into the open wound, deposit a provisional fibrin layer, and stop dividing or become necrotic.…”