Studies on the roles of stromal CXCL14 in tumor growth, progression and metastasis formation

Abstract: Cancer consists of several diseases that are characterized by accumulation of genetic and epigenetic alterations that provide cells with certain capabilities to form tumors. Among these acquired capabilities are enhanced invasion that allow cancer cells to escape from the primary tumor, enter the circulation and eventually reach distant tissues where they form metastasis. Breast and prostate cancer are the most common cancers in Sweden with about 9000 new cases diagnosed each year. The major cause of cancer-related mortality is metastatic disease and new treatments interfering with the underlying mechanisms of metastasis are highly warranted. Enhanced metastasis formation has been shown to occur by reactivation of the developmental program epithelial-to-mesenchymal transition (EMT), regulated by various stimuli, including secreted factors from the tumor stroma. Cancer-associated fibroblasts (CAFs) are the most common stromal cell type that interacts with tumor cells to promote tumor progression and metastasis formation. CAFs have been identified as an important source of EMT-inducing factors including, among others, chemokines. CXCL14 is a CAF-secreted chemokine that promote tumor progression both via autocrine effects on CAFs and paracrine signaling with tumor cells. The studies in this thesis aimed to achieve a better understanding of the functions of fibroblast-derived CXCL14 in tumor biology and the clinical relevance of this chemokine, with a focus on breast and prostate cancer. The first study explored the molecular mechanisms underlying the protumoral effects of fibroblasts expressing CXCL14. NOS1 was discovered as an intracellular component of CXCL14 signaling in CAFs that maintain their tumor supporting functions. Enhanced oxidative stress in CXCL14-fibroblasts upregulated NOS1 that augmented tumor growth and tumor-infiltration of macrophages. The second study reports that CXCL14 expression in the tumor stroma is an independent negative maker for breast cancer survival. Based on sub-group specific analyses it was shown that the correlation between stromal CXCL14-expression and poor prognosis of breast cancer was more prominent in basal-like and triple negative breast cancers. Interestingly, only stromal expression and not tumor cell expression of CXCL14 correlated with worse survival. In the third study, fibroblast secreted CXCL14 was shown to promote cancer cell EMT, invasion and metastasis, effects directly induced by CXCL14 signaling. Moreover, ACKR2 was identified as a receptor for the orphan chemokine and CXCL14/ACKR2 signaling correlated with an EMT gene expression signature in breast cancer patients. In general, these studies have uncovered important functions of CXCL14 in both maintaining a tumor-promoting CAF-phenotype, via induction of NOS1, as well as enhancing tumor progression by induction of tumor cell EMT, invasion and metastasis. Furthermore, ACKR2 was identified as a CXCL14-signaling receptor. Clinical relevance of the experimental findings was established by correlations of CXCL14/ACKR2 signaling with EMT and the identification of stromal CXCL14 expression as an independent marker for survival of breast cancer patients.