CXCR4 and its ligand CXCL12 display opposite expression profiles in feline mammary metastatic disease, with the exception of HER2-overexpressing tumors

Abstract

BackgroundThe receptor CXCR4 and its ligand CXCL12 play crucial roles in breast cancer. Despite the fact that the spontaneous feline mammary carcinoma (FMC) is considered a suitable model for breast cancer studies, the importance of the CXCR4/CXCL12 axis in FMC is completely unknown. Therefore, this work aims to elucidate the role of CXCR4 and its ligand in the progression of FMC and metastatic disease.MethodsCXCR4 and CXCL12 expression was analyzed by immunohistochemistry and immunofluorescence on primary tumors (PT), regional and distant metastases of female cats with mammary carcinoma and correlated with serum CXCL12 levels, tumor molecular subtypes and clinicopathological features.ResultsCXCR4 was more expressed in PT than in metastases (p = 0.0067), whereas CXCL12 was highly expressed in metastatic lesions located in liver and lung (p < 0.0001), as reported for human breast cancer. Moreover, cats with CXCR4 positive PT exhibited significantly lower serum CXCL12 levels than cats with CXCR4 negative mammary carcinomas (p = 0.0324). At metastatic lesions, HER2-overexpressing tumors presented higher CXCR4 expression than the other molecular tumor subtypes (p = 0.012) and significant differences in overall (p = 0.0147) and disease-free survival (p = 0.0279) curves between the cats with CXCL12 positive and CXCL12 negative tumors were found. Indeed, CXCL12 negative PT were associated with unfavorable prognosis in cats with HER2-overexpressing tumors.ConclusionsThis work exposes part of the complex interaction between CXCR4 and CXCL12 in PT, but also in metastases of a breast cancer model. These findings could uncover novel therapeutic tools to be used in cats and humans.

Establishment and Characterization of a Feline Mammary Tumor Patient-Derived Xenograft Model

“…A previous study detailing 10 weeks of subcutaneous engraftment of FMT cells reported no metastasis was observed [9]. Although metastasis to the lymphatics, lungs and liver commonly occurred in this study, we did not nd overt signs of metastasis to brain or bone, which are sites of metastasis in FMT [10][11][12][13]. Future work may be required a speci c and sensitivity label of FMT tumor cells to detect micro-metastasis lesions.…”

Molecular targets for anticancer therapies in companion animals and humans: what can we learn from each other?

“…Targeting CXCR4 in human breast cancer patients is currently under evaluation in clinical trials 129 . In FMC tissues, CXCR4 is frequently highly expressed, whereas CXCR4 expression is not detected in healthy mammary tissues of cats 130 , 131 . Moreover, CXCR4 has been described as one of the top upstream regulators in canine mammary tumors 132 .…”

Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor (CAR) for tumor immunotherapy; recent progress

“…Correspondingly, study of the possible relation between the COX-2 and HER-2 in colorectal cancer (CRC) indicated that in addition to the presence of a robust association between COX-2 and HER-2 expression in CRC, both of them are an important player in the invasion and metastasis of CRC [ 90 ]. In addition, HER2 elicits the expression of the chemokine receptor C-X-C motif chemokine receptor 4 (CXCR4) in transfection models and also up-regulated CXCR4 expression is typically found in breast cancers with high rates of HER2 expression [ 91 ]. Thanks to that CXCR4/CXCL12 chemokine interaction facilitates tumor cell proliferation and leads to the development of distant metastases, it appears that metastasis of breast cancers may mainly arise from the overexpression of chemokine receptors.…”