Interspecies cross-reactivity is an important consideration when interpreting the results of tissue xenograft studies. For many paracrine signaling pathways, murine growth factors may not activate their orthologous human receptors in tumor xenografts, thereby failing to recapitulate a potentially relevant human condition in the mouse model. Unrecognized or poorly defined species-specific differences of this type can seriously hinder basic research progress as well as the development of therapeutic or diagnostic agents. For example, the contributions of both tumor- and stromal-cell derived vascular endothelial growth factor (VEGF)-A to the vascularization of human tumor xenografts in immunodeficient mice prevented the direct comparison of anti-VEGF antibodies with different abilities to block host VEGF, and led to the production of mice expressing humanized VEGF with biological activity comparable to both human and mouse VEGF-A.
Hepatocyte growth factor (HGF) and its receptor, Met, are also highly sought targets in cancer drug and diagnostic development. HGF/Met signaling drives tumor cell growth and motility, tumor invasiveness and metastasis. However, the failure of murine HGF to stimulate the growth of human tumor xenografts has restricted preclinical drug studies to a handful of human tumor cell lines that possess autocrine pathway activation or other more rare Met activation mechanisms, and ultimately forced the costly development of human HGF transgenic and knock-in mice so that preclinical studies could begin to encompass the known breadth of the pathway's involvement across human cancers.
We report here that despite the failure of murine HGF to drive human tumor xenograft growth, mouse HGF potently stimulates human Met autophosphorylation, increased cell motility and matrix invasion, but not proliferation. As a result, the growth of xenografted PC3M human prostate adenocarcinoma cells as primary tumors in mice was not inhibited by a selective HGF antagonist, but spontaneous tumor metastasis was completely blocked. These results improve our understanding of the cross-reactivity between human and murine HGF/Met signaling pathways and suggest that the preclinical evaluation of agents for their ability to block HGF-driven tumor metastasis may incorporate cell lines expressing human Met but not HGF, i.e. a wide variety of human carcinoma-derived cell lines, without the need for using mice engineered to express human HGF.
Citation Format: Fabiola Cecchi, Chih-Jian Lih, Young H. Lee, William D. Walsh, Michael P. Williams, Donald P. Bottaro. Experimental metastasis by the prostate adenocarcinoma-derived cell line PC3M is driven by partial activation of the human Met pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4085. doi:10.1158/1538-7445.AM2013-4085