1. Inhibition of Hematopoietic Cell Kinase Activity Suppresses Myeloid Cell-Mediated Colon Cancer Progression
- Author
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Poh, Ashleigh R, Love, Christopher G, Masson, Frederick, Preaudet, Adele, Tsui, Cary, Whitehead, Lachlan, Monard, Simon, Khakham, Yelena, Burstroem, Lotta, Lessene, Guillaume, Sieber, Oliver, Lowell, Clifford, Putoczki, Tracy L, O'Donoghue, Robert JJ, and Ernst, Matthias
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Immunology ,Oncology and Carcinogenesis ,Colo-Rectal Cancer ,Hematology ,Rare Diseases ,Digestive Diseases ,Cancer ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Colonic Neoplasms ,Colorectal Neoplasms ,Female ,Gene Expression Regulation ,Neoplastic ,Humans ,Macrophage Activation ,Mice ,Inbred C57BL ,Mice ,Knockout ,Proto-Oncogene Proteins c-hck ,Pyrimidines ,Pyrroles ,STAT3 Transcription Factor ,Signal Transduction ,Stromal Cells ,Xenograft Model Antitumor Assays ,SRC family kinases ,alternative macrophage polarization ,colitis-associated colon cancer ,colorectal cancer ,hematopoietic cell kinase ,mouse model ,stat3 ,tumor microenvironment ,tyrosine kinase inhibitor ,xenograft ,Neurosciences ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Aberrant activation of the SRC family kinase hematopoietic cell kinase (HCK) triggers hematological malignancies as a tumor cell-intrinsic oncogene. Here we find that high HCK levels correlate with reduced survival of colorectal cancer patients. Likewise, increased Hck activity in mice promotes the growth of endogenous colonic malignancies and of human colorectal cancer cell xenografts. Furthermore, tumor-associated macrophages of the corresponding tumors show a pronounced alternatively activated endotype, which occurs independently of mature lymphocytes or of Stat6-dependent Th2 cytokine signaling. Accordingly, pharmacological inhibition or genetic reduction of Hck activity suppresses alternative activation of tumor-associated macrophages and the growth of colon cancer xenografts. Thus, Hck may serve as a promising therapeutic target for solid malignancies.
- Published
- 2017