Enhancing cancer‐associated fibroblast fatty acid catabolism within a metabolically challenging tumor microenvironment drives colon cancer peritoneal metastasis

Autor: Huaiming Wang, Shaoyong Peng, Hui Wang, Qianxin Luo, Zhihang Liu, Yanmei Cui, Wenfeng Liang, Daici Chen, Yingyi Kuang, Jian Cai, Qian Wang, Binjie Huang, Zixu Yuan, Yichen Li, Xiaoxia Liu
Rok vydání: 2021
Předmět:
Male
0301 basic medicine
Cancer Research
Colorectal cancer
CPT1A
Mice
chemistry.chemical_compound
0302 clinical medicine
Cancer-Associated Fibroblasts
Cell Movement
Tumor Microenvironment
Glycolysis
CAF
RC254-282
Research Articles
Cells
Cultured
Peritoneal Neoplasms
Mice
Inbred BALB C
Fatty Acids
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
General Medicine
glycolysis
Middle Aged
Up-Regulation
peritoneal metastases
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Colonic Neoplasms
Molecular Medicine
Female
Oxidation-Reduction
Research Article
medicine.drug
Adult
Adolescent
Mice
Nude
colorectal cancer
Young Adult
03 medical and health sciences
Peritoneal cavity
Genetics
medicine
Animals
Humans
Carnitine
Aged
Cell Proliferation
Tumor microenvironment
Adiponectin
business.industry
HCT116 Cells
Lipid Metabolism
medicine.disease
FAO
030104 developmental biology
chemistry
Cancer cell
Cancer research
business
Etomoxir
Zdroj: Molecular Oncology
Molecular Oncology, Vol 15, Iss 5, Pp 1391-1411 (2021)
ISSN: 1878-0261
1574-7891
DOI: 10.1002/1878-0261.12917
Popis: Most cancer‐related deaths result from the progressive growth of metastases. Patients with peritoneal metastatic (PM) colorectal cancer have reduced overall survival. Currently, it is still unclear why colorectal cancer (CRC) cells home to and proliferate inside the peritoneal cavity, and there is no effective consolidation therapy for improved survival. Using a proteomic approach, we found that key enzymes of fatty acid oxidation (FAO) were decreased in patients with PM colorectal cancer. Furthermore, we confirmed that carnitine palmitoyltransferase IA (CPT1A), a rate‐limiting enzyme of FAO, was expressed at significantly low levels in patients with PM colorectal cancer, as determined by RT‐qPCR, IHC, and GEO dataset analysis. However, lipidomics revealed no difference in FFA levels between PM and non‐PM primary tumors. Here, we showed that cancer‐associated fibroblasts (CAFs) promote the proliferation, migration, and invasion of colon cancer cells via upregulating CPT1A to actively oxidize FAs and conduct minimal glycolysis. In addition, coculture‐induced glycolysis increased in cancer cells while fatty acid catabolism decreased with lower adiponectin levels. Importantly, inhibition of glycolysis significantly reduced the survival of CRC cells after incubation with conditioned medium from CAFsCPT1A ‐OE in vitro and impaired the survival and growth of organoids derived from CRC‐PM. Finally, we found that directly blocking FAO in CAFsCPT1A ‐OE with etomoxir inhibits migration and invasion in vitro and decreases tumor growth and intraperitoneal dissemination in vivo, revealing a role for CAF CPT1A in promoting tumor growth and invasion. In conclusion, our results suggest the possibility of testing FAO inhibition as a novel approach and clinical strategy against CAF‐induced colorectal cancer with peritoneal dissemination/metastases.
Patients with peritoneal metastatic (PM) colorectal cancer have reduced overall survival. In metabolically challenging tumor microenvironment, cancer‐associated fibroblasts (CAFs) enhance fatty acid catabolism by upregulating CPT1A expression and drive colon cancer peritoneal metastasis. Our results suggest the possibility of testing fatty acid oxidation inhibition as a novel approach and clinical strategy against CAF‐induced colorectal cancer with peritoneal dissemination/metastases.
Databáze: OpenAIRE
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