Expression array analysis of the hepatocyte growth factor invasive program

Abstract

Signaling by human hepatocyte growth factor (hHGF) via its cell surface receptor (MET) drives mitogenesis, motogenesis and morphogenesis in a wide spectrum of target cell types and embryologic, developmental and homeostatic contexts. Oncogenic pathway activation also contributes to tumorigenesis and cancer progression, including tumor angiogenesis and metastasis, in several prevalent malignancies. The HGF gene encodes full-length hHGF and two truncated isoforms known as NK1 and NK2. NK1 induces all three HGF activities at modestly reduced potency, whereas NK2 stimulates only motogenesis and enhances HGF-driven tumor metastasis in transgenic mice. Prior studies have shown that mouse HGF (mHGF) also binds with high affinity to human MET. Here we show that, like NK2, mHGF stimulates cell motility, invasion and spontaneous metastasis of PC3M human prostate adenocarcinoma cells in mice through human MET. To identify target genes and signaling pathways associated with motogenic and metastatic HGF signaling, i.e., the HGF invasive program, gene expression profiling was performed using PC3M cells treated with hHGF, NK2 or mHGF. Results obtained using Ingenuity Pathway Analysis software showed significant overlap with networks and pathways involved in cell movement and metastasis. Interrogating The Cancer Genome Atlas project also identified a subset of 23 gene expression changes in PC3M with a strong tendency for co-occurrence in prostate cancer patients that were associated with significantly decreased disease-free survival.

Increased Lactate Secretion by Cancer Cells Sustains Non-cell-autonomous Adaptive Resistance to MET and EGFR Targeted Therapies

“…These results demonstrate the causative role of CAF-produced HGF in this model of resistance. Notably, while mouse HGF was reported to activate only some of the MET-driven biological activities in human cells (Cecchi et al, 2015), we clearly observed that, in the specific context of resistance to MET TKIs, mouse and human purified HGF exerted superimposable effects on human MET-addicted cells, inducing a similar shift of the TKI IC 50 ( Figure 2G).…”

Dimer Interface in Natural Variant NK1 Is Dispensable for HGF-Dependent Met Receptor Activation

“…HGF and NK1, but not NK2, induce epithelial tubulogenesis [28]. NK2 enhances the migration of cells and antagonizes the mitogenic response induced by HGF or NK1 [29][30][31]. A synthetic Met agonist composed of cyclic peptide weakly activated Met but enhanced cell motility at levels comparable to that of HGF [32].…”

Stroma-derived HGF drives metabolic adaptation of colorectal cancer to angiogenesis inhibitors

“…To investigate this possibility, we exploited the inability of mouse HGF to fully activate human MET [26–28]. In fact, MET activation in colorectal tumors occurs primarily via paracrine HGF stimulation by the surrounding stroma [29].…”

“…In this study we hypothesized that HGF/MET signaling could be responsible not only for allowing CRC cells to physically escape anti-angiogenic therapy, but also for rewiring their metabolism in response to vessel pruning. To investigate this possibility, we exploited the inability of mouse HGF to fully activate human MET [ 26 – 28 ]. In fact, MET activation in colorectal tumors occurs primarily via paracrine HGF stimulation by the surrounding stroma [ 29 ].…”