Hepatocyte Growth Factor/cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Carcinoma.
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.
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Liem M
LM
Phan
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Enrique
E
Fuentes-Mattei
Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Weixin
W
Wu
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Guermarie
G
Velazquez-Torres
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Kanishka
K
Sircar
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Christopher G
CG
Wood
Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Tao
T
Hai
Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Camilo
C
Jimenez
Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Gilbert J
GJ
Cote
Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Levent
L
Ozsari
Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Marie-Claude
MC
Hofmann
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Siyuan
S
Zheng
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Roeland
R
Verhaak
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Lance
L
Pagliaro
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Maria Angelica
MA
Cortez
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Mong-Hong
MH
Lee
Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Sai-Ching J
SC
Yeung
Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas. mahabra@mdanderson.org.
Mouhammed Amir
MA
Habra
D000236:Adenoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000306:Adrenal Cortex Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002277:Carcinoma / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D008939:Mitotane / Q000494:pharmacology; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D059467:Transcriptome; D023041:Xenograft Model Antitumor Assays
D000813:Anilides; D000970:Antineoplastic Agents; C066855:HGF protein, human; D009363:Neoplasm Proteins; D011725:Pyridines; D034741:RNA, Small Interfering; C558660:cabozantinib; D017228:Hepatocyte Growth Factor; D008939:Mitotane; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D002945:Cisplatin