Hemopoietic cell kinase, HCK, a Src-family kinase expressed in myeloid and B-lymphoid cells, regulates innate immune cell, and is aberrantly activated and/or expressed in solid tumors incl colon, stomach and lung. Using the Hck(CA) mouse model, which carries a constitutively activating germline mutation and spontaneously develops pulmonary inflammation, airspace enlargement highly reminiscent of patient with chronic obstructive pulmonary disease, COPD [1].

To establish whether aberrant Hck activation promotes tumorigenesis, we tested three established cancer models.   First, we found increased lung adenocarcinoma burden in Hck(CA)x Kras(LSL-G12D) mice compared to Kras(LSL-G12D) mice, where the oncogenic KrasV12D transgene is activated after transnasal administration of Adeno virus-encoded Cre.   Second, using gp130(F/+) mice as a strain predisposed to gastric cancer development [2], we established that compound Hck(CA)x gp130(F/+) developed tumor burden similar to that of gp130(F/F) animals. Furthermore, tumors from Hck(CA)x gp130(F/+) mice, but not from gp130(F/F) mice, showed sub-mucosal invasion.   Third, we modeled sporadic colorectal cancer by repetitive administration of the somatic mutagen azoxymethane [3]. Compared to wild-type mice, Hck(CA)mice exhibited increased tumor frequency and multiplicity, and colonic tumors in Hck(CA)mice showed mucosal invasion, which was absent from tumors in wild-type mice. In all models the Hck(CA) allele increased tumor cell proliferation and associated Stat3, Erk, Akt and S6 cytoplasmic signaling, although the total number of tumor-associated macrophages remained unchanged by the presence of the Hck(CA) allele. However gene expression profiling of the latter cells revealed excessive alternative macrophage activation from Hck(CA) mice with prominent expression of Il4, Il10, Il13, Arg1 and Ym1. Accordingly, adoptive transfer of Hck(CA)bone-marrow was sufficient to confer increase tumor burden and promote alternative macrophage polarization. Conversely, reconstitution with Hck-deficient bone-marrow reduced tumor burden and these observations were replicated with a small molecule inhibitor directed against Hck.

Collectively, our data suggest that mutations affecting the stroma, and macrophage polarization specifically, confer tumor progression and that HCK may provide a novel target for rational cancer drug development.