Combination therapy using molecular-targeted drugs modulates tumor microenvironment and impairs tumor growth in renal cell carcinoma.

Abstract

Tumor growth and metastasis are determined not by cancer cells alone but also by a variety of stromal cells, various populations of which overexpress platelet-derived growth factor receptors (PDGF-Rs). In addition, activation of PI3K-AKT-mammalian target of rapamycin (mTOR) signaling is frequently observed in many cancer types as well. mTOR comprises a serine/threonine kinase that increases the production of proteins that stimulate key cellular processes such as cell growth and proliferation, cell metabolism, and angiogenesis. In this study, we investigated the impact of molecular-targeting agents including PDGF-R and mTOR inhibitors on the tumor stroma of human kidney cancer and examined the efficacy of combination therapy with these agents against this disease. Treatment with sunitinib did not suppress tumor growth, but significantly decreased stromal reactivity, microvessel density, and pericyte coverage of tumor microvessels in an orthotopic mouse model. In contrast, treatment with everolimus decreased tumor growth and microvessel density but not stromal reactivity. However, sunitinib and everolimus in combination reduced both the growth rate and stromal reaction. These findings suggest that target molecule-based inhibition of the cancer-stromal cell interaction appears promising as an effective antitumor therapy.

• Authors: Hiroyuki Kitano, Yasuhiko Kitadai, Jun Teishima, Ryo Yuge, Shunsuke Shinmei, Keisuke Goto, Shogo Inoue, Tetsutaro Hayashi, Kazuhiro Sentani, Wataru Yasui, Akio Matsubara
• Journal: Cancer medicine (Cancer Med) Vol. 6 Issue 10 Pg. 2308-2320 (Oct 2017) ISSN: 2045-7634 [Electronic] United States
• PMID: 28834289 (Publication Type: Journal Article)
• Copyright: © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chemical References

• Antineoplastic Agents
• Indoles
• Platelet-Derived Growth Factor
• Pyrroles
• Everolimus
• TOR Serine-Threonine Kinases
• Sunitinib

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Carcinoma, Renal Cell (diagnostic imaging, drug therapy, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Drug Therapy, Combination
• Everolimus (pharmacology)
• Female
• Humans
• Immunohistochemistry
• Indoles (pharmacology)
• Kidney Neoplasms (diagnostic imaging, drug therapy, pathology)
• Luminescent Measurements (methods)
• Mice
• Molecular Imaging (methods)
• Molecular Targeted Therapy
• Neovascularization, Pathologic (drug therapy, metabolism)
• Platelet-Derived Growth Factor (metabolism)
• Pyrroles (pharmacology)
• Signal Transduction (drug effects)
• Stromal Cells (drug effects, metabolism)
• Sunitinib
• TOR Serine-Threonine Kinases (metabolism)
• Tumor Burden (drug effects)
• Tumor Microenvironment (drug effects)
• Xenograft Model Antitumor Assays