The critical role of mast cell-derived hypoxia-inducible factor-1α in regulating mast cell function.
OBJECTIVE
During colorectal tumour progression, the tumour microenvironment becomes hypoxic, and infiltration of a large number of inflammatory cells occurs. The mast cells (MCs) are a type of immune cells plays an important role in tumour angiogenesis. However, it is unclear whether the role of MC in colorectal cancer is to promote or to inhibit tumour growth.


METHODS
Immunohistochemical analysis of clinical colorectal cancer samples and a colorectal carcinoma model were used.


RESULTS
We found the carcinomas and the adjacent tissues were infiltrated with large numbers of mast cells, and the MC infiltration quantity increased with the Dukes' stage. After tumour inoculation, the survival time of MC-deficient mice was remarkably longer than wild-type C57BL/6 mice, and the tumour growth rate of MC-deficient mice was slower than wild type. In addition, the survival time and tumour growth rate can be recovered in MC reconstruction mice. Furthermore, inhibition of the expression of hypoxia-inducible factor-1α (HIF-1α) using siRNA reduced the release of inflammatory factors and the degree of MC degranulation.


CONCLUSIONS
Mast cells promote the development of colorectal cancer, and MC-derived HIF-1α plays an important role in regulating MC function. Our study reveals a novel role of MC-derived HIF-1α in the colorectal carcinoma microenvironment.
Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.|State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
Xin
X
Liang
State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
Guifang
G
Yin
Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Yuanyuan
Y
Ma
Central Laboratory, Putuo Hospital and Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine Shanghai University of Traditional Chinese Medicine, Shanghai, China. cola519@163.com.
Ke
K
Xu
State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China. liujian@ecust.edu.cn.
Jianwen
J
Liu
Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. leejiyu@sina.com.
Jiyu
J
Li
D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D019898:Autocrine Communication; D002460:Cell Line; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D005838:Genotype; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009367:Neoplasm Staging; D019899:Paracrine Communication; D010641:Phenotype; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D059016:Tumor Microenvironment
D042501:Angiogenic Proteins; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators
colorectal cancer; cytokine; hypoxia-inducible factor-1α; mast cell