CX3CL1 Promotes Breast Cancer via Transactivation of the EGF Pathway

Abstract

Chemokines are relevant molecules in shaping the tumor microenvironment, although their contributions to tumorigenesis are not fully understood. We studied the influence of the chemokine CX3CL1/fractalkine in de novo breast cancer formation using HER2/neu transgenic mice. CX3CL1 expression was downmodulated in HER2/neu tumors, yet, paradoxically, adenovirus-mediated CX3CL1 expression in the tumor milieu enhanced mammary tumor numbers in a dose-dependent manner. Increased tumor multiplicity was not a consequence of CX3CL1-induced metastatic dissemination of the primary tumor, although CX3CL1 induced epithelial-to-mesenchymal transition in breast cancer cells in vitro. Instead, CX3CL1 triggered cell proliferation by induction of ErbB receptors through the proteolytic shedding of an ErbB ligand. This effect was important insofar as mammary tumorigenesis was delayed and tumor multiplicity was reduced by genetic deletion of CX3CL1 in HER2/neu mice, but not in polyoma middle T-antigen oncomice. Our findings support the conclusion that CX3CL1 acts as a positive modifier of breast cancer in concert with ErbB receptors.

The Fractalkine-Receptor Axis Improves Human Colorectal Cancer Prognosis by Limiting Tumor Metastatic Dissemination

“…The antitumor effects of CX 3 CL1 are mostly related to attraction of cytotoxic CD8 T lymphocytes and NK cells (40,42,43). However, CX 3 CL1 may also stimulate tumor survival and proliferation, and in breast cancer it promotes tumor progression via trans-activation of the epidermal growth factor pathway (32,52). The dual nature of the CX 3 CR1-CX 3 CL1 axis is an example of the complex interplay between neoplastic cells, the tumor stroma, and infiltrating leukocytes.…”

Filamin A interaction with the CXCR4 third intracellular loop regulates endocytosis and signaling of WT and WHIM-like receptors

“…ERK activation, actin polymerization, and chemotaxis assays were performed as described. 36,37 Results CXCR4 C-tail is not the only FLNA binding motif Studies have shown that the CXCR4 C-tail binds to the atypical FLNA repeat 10. 22,38 Sequence analysis predicted a small motif at the CXCR4 C-tail, with charge and secondary structure similar to those identified in CD4 as important for binding to FLNA repeat 10 (supplemental Figure 1A).…”

A lovastatin-elicited genetic program inhibits M2 macrophage polarization and enhances T cell infiltration into spontaneous mouse mammary tumors

“…Cell populations from tumors were purified as described [58]. Total RNA from total tumor samples or tumor cell fractions was extracted with Tri-Reagent or with the Easy RNA kit (Qiagen, when recovered cells ≤5 × 10 5 ) and used to synthesize the first cDNA strand (High-capacity cDNA Archive Kit, Applied Biosystems) using random primers.…”