Signaling by hepatocyte growth factor (HGF) via its cell surface receptor, Met, drives cell survival, growth and motility, as well as tumor growth and metastasis in several prevalent human cancers. HGF and Met have become highly sought targets for cancer drug development: 165 clinical trials of 21 experimental agents have been completed or are in progress. We reported previously that a selective HGF antagonist failed to block growth of the human prostate adenocarcinoma derived cell line PC3M as primary tumor xenografts in mice, but potently blocked spontaneous PC3M tumor metastasis, as well as cell motility and invasion in vitro. Thus partial activation of the Met pathway in PC3M cells by murine HGF (mHGF) is capable of driving invasion but not proliferation, whereas human HGF (hHGF) is capable of driving both activities.

To identify the signaling and gene modulation events critical for Met-driven cell invasion and to distinguish them from Met-driven proliferation, mRNA expression array and pathway profiling analyses of hHGF and mHGF-treated PC3M cells were performed. Ingenuity Pathway Analysis (IPA) of 344 hHGF-specific statistically significant gene modulation events of 2-fold or greater showed significant overlap with cell cycle progression and proliferation pathways, cancer and upstream activation of the cyclin D1 and choriogonadotropin pathways. IPA analysis of 520 gene modulation events associated with motility and invasion showed significant overlap with cell migration and invasion pathways, upstream activation of the MEK/MAPK and mir-155 pathways and upstream inhibition of PI3K and pro-inflammatory cytokine pathways.

HGF-specific blockade of spontaneous PC3M metastasis in our model prompted us to further compare significant gene modulation events related to cell invasion with those reported for prostate cancer tumor samples as part of The Cancer Genome Atlas Project (TCGA; MSKCC, 2010; 216 cases). Of 520 altered genes in PC3M, 345 were also interrogated in TCGA: 150 of these (47%) were similarly modulated in prostate cancer patient samples. Twenty-four gene modulation events (7%) were associated with significant change in disease-free survival (DFS) in 88% of cases: 1 gene with increased DFS (logrank p: 0.002747, 56% of cases affected) and 23 with decreased DFS (logrank p: 0.007542; 65% of cases affected).

Together these findings identify critical differences in intracellular pathways downstream of HGF/Met interaction leading to cell proliferation vs invasion and reveal that a substantial fraction of prostate cancer patients who show gene modulation events associated with increased tumor cell invasion and metastasis in the PC3M model described here also experience significantly accelerated disease progression.

Citation Format: Fabiola Cecchi, Jason Lih, Young Lee, William Walsh, Mickey Williams, Donald P. Bottaro. Gene expression array and pathway profiling analyses distinguish HGF/Met pathways driving cell proliferation from invasion and identify events correlated with prostate cancer progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5259. doi:10.1158/1538-7445.AM2014-5259