Hepatocyte Growth Factor/cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Carcinoma.

Abstract

Adrenocortical carcinoma is a rare malignancy with poor prognosis and limited response to chemotherapy. Hepatocyte growth factor (HGF) and its receptor cMET augment cancer growth and resistance to chemotherapy, but their role in adrenocortical carcinoma has not been examined. In this study, we investigated the association between HGF/cMET expression and cancer hallmarks of adrenocortical carcinoma. Transcriptomic and immunohistochemical analyses indicated that increased HGF/cMET expression in human adrenocortical carcinoma samples was positively associated with cancer-related biologic processes, including proliferation and angiogenesis, and negatively correlated with apoptosis. Accordingly, treatment of adrenocortical carcinoma cells with exogenous HGF resulted in increased cell proliferation in vitro and in vivo while short hairpin RNA-mediated knockdown or pharmacologic inhibition of cMET suppressed cell proliferation and tumor growth. Moreover, exposure of cells to mitotane, cisplatin, or radiation rapidly induced pro-cMET expression and was associated with an enrichment of genes (e.g., CYP450 family) related to therapy resistance, further implicating cMET in the anticancer drug response. Together, these data suggest an important role for HGF/cMET signaling in adrenocortical carcinoma growth and resistance to commonly used treatments. Targeting cMET, alone or in combination with other drugs, could provide a breakthrough in the management of this aggressive cancer.

• Authors: Liem M Phan, Enrique Fuentes-Mattei, Weixin Wu, Guermarie Velazquez-Torres, Kanishka Sircar, Christopher G Wood, Tao Hai, Camilo Jimenez, Gilbert J Cote, Levent Ozsari, Marie-Claude Hofmann, Siyuan Zheng, Roeland Verhaak, Lance Pagliaro, Maria Angelica Cortez, Mong-Hong Lee, Sai-Ching J Yeung, Mouhammed Amir Habra
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 19 Pg. 4131-42 (Oct 01 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 26282167 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Anilides
• Antineoplastic Agents
• HGF protein, human
• Neoplasm Proteins
• Pyridines
• RNA, Small Interfering
• cabozantinib
• Hepatocyte Growth Factor
• Mitotane
• MET protein, human
• Proto-Oncogene Proteins c-met
• Cisplatin

Topics

• Adenoma (drug therapy, metabolism, pathology)
• Adrenal Cortex Neoplasms (blood supply, drug therapy, metabolism, pathology)
• Adult
• Aged
• Aged, 80 and over
• Anilides (pharmacology, therapeutic use)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinoma (blood supply, drug therapy, metabolism, pathology)
• Cell Division
• Cell Line, Tumor
• Cisplatin (pharmacology)
• Drug Resistance, Neoplasm (drug effects, radiation effects)
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects, radiation effects)
• Hepatocyte Growth Factor (physiology)
• Humans
• Male
• Mice
• Mice, Nude
• Middle Aged
• Mitotane (pharmacology)
• Molecular Targeted Therapy
• Neoplasm Proteins (physiology)
• Neovascularization, Pathologic (physiopathology)
• Proto-Oncogene Proteins c-met (physiology)
• Pyridines (pharmacology, therapeutic use)
• RNA Interference
• RNA, Small Interfering (pharmacology)
• Signal Transduction (physiology)
• Transcriptome
• Xenograft Model Antitumor Assays