ELR-CXC chemokines: regulators of tumour progression

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Among dogs affected with prostatic inflammatory diseases, the incidence of prostate cancer is substantially elevated (5-7%) relative to the general population. The prognosis for dogs with metastatic prostate cancer is not unlike that in humans - progression can sometimes be slowed, but it is not abated by any of the approaches we now use. Unlike the human condition, we know little about the immunobiology of canine tumours. A number of G protein-coupled receptors (GPCR; e.g., CXCR1, CXCR2) have been directly implicated in human prostate tumour progression, but some of these can also transactivate unrelated growth factor receptors (e.g., EGF-R) that also foster tumour progression. We know that with human tumours the ELR-CXC chemokines (e.g., CXCL8) contribute in multiple ways to tumour growth, angiogenesis, metastasis, and the development resistance to chemotherapeutic agents, and their expression is both elevated in and prognostic of outcomes with at least some canine cancers. This suggests that these mediators could similarly play important roles in the cellular and molecular biology of cancer in dogs. - Our lab developed an anti-inflammatory agent, bovine `G31P', that antagonizes the CXCR1 and CXCR2 receptors for the ELR-CXC chemokines but, unlike any competitor CXCR1/CXCR2 antagonists, it also desensitizes or dampens activation of unrelated GPCR (e.g., the C5aR) in CXCR1/R2-positive cells. G31P has rather dramatic pathology-sparing effects in numerous models of inflammation, but it also ~90% reduces human PC-3 prostate cancer progression in a xenogeneic SCID (immunocompromised) mouse model. Thus, we now have some important new tools with which we can interrogate the basic biology of the ELR-CXC chemokines. - Our program is designed to explore the roles of these chemokines in canine cancer, specifically assessing whether CXCR1/CXCR2 antagonism will block tumour progression. Realization of this objective will contribute foundational knowledge in this largely unknown area of canine biology. We hypothesize that the ELR-CXC chemokines are cornerstones of tumourigenesis in dogs, having profound effects in i) primary tumour growth, ii) angiogenesis, and iii) the development of resistance to chemotherapics. We will address each of these facets using a canine prostate cancer/SCID mouse model, established canine prostate tumour cell lines and cells obtained from oncology clinic donors. Specifically, we will map the levels at which tumour cells express or induce local expression of ELR-CXC chemokines and their receptors, as well as other tumour-relevant GPCR receptors and their ligands by use of canine and mouse host PCR array, qRT-PCR and/or ELISA assays. The abilities of the tumour cells to secrete angiogenic factors will also be assessed, as will the contributions of these chemokines and heterologous GPCR to these processes in tumours. We will also confirm that they contribute to primary tumour progression, analyzing cytokine, chemokine & chemokine receptor useage. We will map the activity of relevant heterologous GPCR in tumours and assess whether their silencing changes tumour biology. Development of resistance to cytotoxins is a major confounder in cancer therapy; as such we will examine the roles of these chemokines therein, determining whether their antagonism will benefit cancer chemotherapeutic outcomes, as well as the cellular and molecular mechanisms underlying these processes. - This information will provide important new insights into the biology of tumours and ELR-CXC chemokines in dogs, and potentially lead to new avenues of discovery in cancer therapy. The proposed program will provide training for a number of next-generation researchers and potentially open an entirely new door in canine immunobiology research.