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.
Highlights
The receptor C-X-C Chemokine Receptor Type 4 (CXCR4) and its ligand Chemokine ligand 12 (CXCL12) play crucial roles in breast cancer
In 2017, a preclinical study showed that two CXCR4 inhibitors (AMD3100 and TN14003) significantly reduced tumor growth in a Human epidermal growth factor receptor type II (HER2) overexpressing tumor xenographs, including Herceptin and Docetaxel-resistant, suggesting that CXCR4 inhibition could be a useful strategy for treat HER2 breast cancer patients [16]
Taking into account the relevant oncogenic role of the CXCR4/CXCL12 axis in breast cancer progression and its potential to be targeted by anti-tumor molecules, we aimed to clarify the signature of CXCR4 and CXCL12 in cats with mammary metastatic disease and search for significant associations between CXCR4 and CXCL12 tissue status and serum CXCL12 values, clinicopathological features and feline mammary carcinoma (FMC) molecular subtypes
Summary
The receptor CXCR4 and its ligand CXCL12 play crucial roles in breast cancer. Evidence for a regulatory role of CXCR4/CXCL12 axis in the progression of the Marques et al BMC Cancer (2018) 18:741 the role of CXCR4/CXCL12 axis in human breast cancer and metastatic disease [1, 2, 10,11,12], suggesting that targeted therapies against CXCR4/CXCL12 axis may inhibit tumor growth. Several preclinical studies targeting the CXCR4/CXCL12 axis have been recently conducted in breast tumors. In 2017, a preclinical study showed that two CXCR4 inhibitors (AMD3100 and TN14003) significantly reduced tumor growth in a HER2 overexpressing tumor xenographs, including Herceptin and Docetaxel-resistant, suggesting that CXCR4 inhibition could be a useful strategy for treat HER2 breast cancer patients [16]. Nef-M1, a CXCR4 antagonist peptide, showed good therapeutic potential for inhibiting tumor angiogenesis and the oncogenic epithelial-to-mesenchymal transition process in patient derived xenographs [17]
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