Inhibition of Hematopoietic Cell Kinase Activity Suppresses Myeloid Cell-Mediated Colon Cancer Progression.

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.
Authors	Ashleigh R Poh, Christopher G Love, Frederick Masson, Adele Preaudet, Cary Tsui, Lachlan Whitehead, Simon Monard, Yelena Khakham, Lotta Burstroem, Guillaume Lessene, Oliver Sieber, Clifford Lowell, Tracy L Putoczki, Robert J J O'Donoghue, Matthias Ernst
Journal	Cancer cell (Cancer Cell) Vol. 31 Issue 4 Pg. 563-575.e5 (04 10 2017) ISSN: 1878-3686 [Electronic] United States
PMID	28399411 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright	Copyright © 2017 Elsevier Inc. All rights reserved.
Chemical References	Pyrimidines Pyrroles RK-20449 STAT3 Transcription Factor STAT3 protein, human Stat3 protein, mouse HCK protein, human Hck protein, mouse Proto-Oncogene Proteins c-hck
Topics	Animals Colonic Neoplasms (genetics, metabolism, pathology) Colorectal Neoplasms (genetics, metabolism, mortality, pathology) Female Gene Expression Regulation, Neoplastic Humans Macrophage Activation (genetics) Mice, Inbred C57BL Mice, Knockout Proto-Oncogene Proteins c-hck (antagonists & inhibitors, genetics, metabolism) Pyrimidines (pharmacology) Pyrroles (pharmacology) STAT3 Transcription Factor (metabolism) Signal Transduction Stromal Cells (metabolism) Xenograft Model Antitumor Assays

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