Essential roles of the interaction between cancer cell-derived chemokine, CCL4, and intra-bone CCR5-expressing fibroblasts in breast cancer bone metastasis

Abstract

From a murine breast cancer cell line, 4T1, we established a subclone, 4T1.3, which consistently metastasizes to bone upon its injection into the mammary fat pad. 4T1.3 clone exhibited similar proliferation rate and migration capacity as the parental clone. However, the intra-bone injection of 4T1.3 clone caused larger tumors than that of the parental cells, accompanied with increases in fibroblast, but not osteoclast or osteoblast numbers. 4T1.3clone displayed an enhanced expression of a chemokine, CCL4, but not its specific receptor, CCR5. CCL4 shRNA-transfection of 4T1.3 clone had few effects on its in vitro properties, but reduced the tumorigenicity arising from the intra-bone injection. Moreover, intra-bone injection of 4T1.3 clone caused smaller tumors in mice deficient in CCR5 or those receiving CCR5 antagonist, than in wild-type mice. The reduced tumor formation was associated with attenuated accumulation of CCR5-positive fibroblasts expressing connective tissue growth factor (CTGF)/CCN2. Tumor cell-derived CCL4 could induce fibroblasts to express CTGF/CCN2, which could support 4T1.3 clone proliferation under hypoxic culture conditions. Thus, the CCL4-CCR5 axis can contribute to breast cancer metastasis to bone by mediating the interaction between cancer cells and fibroblasts in bone cavity. Sasaki et al. 3

High levels of CCL2 or CCL4 in the tumor microenvironment predict unfavorable survival in lung adenocarcinoma

“…However, a previous study reported that higher levels of CCL2 in ovarian cancer cell lines were associated with increased chemosensitivity and decreased invasion in vitro, and increased ovarian tumoral expression of CCL2 was associated with improved chemotherapy response and survival outcomes . In addition, the CCL4 axis can contribute to breast cancer metastasis to bone by mediating the interaction between cancer cells and fibroblasts in bone cavity by bonding to CC chemokine receptor type 5 . Inversely, increased CCL4 expression shows a significant association with prolonged OS in patients with esophageal squamous cell carcinoma .…”

Data report on inflammatory C–C chemokines among insulin-using women with diabetes mellitus and breast cancer

“…Clinical and treatment history were evaluated in relationship with cancer outcomes and pro-inflammatory cytokine profiles. A biomarker correlation analysis was performed between the studied C-C chemokines and between each of them and the cytokine levels already reported elsewhere for this particular patient population [1], [2], [3], [4], [5], [6], [7], [8], [9]. The additional correlations were provided for completeness and usability of this data.Data source locationUnited States, Buffalo, NY - 42° 53׳ 50.3592"N; 78° 52׳ 2.658"WData accessibilityThe data is with this article…”

“…Their mobilization is a chemotactic response mediated by tumor-derived factors, among which the C–C chemokines CCL-2, 3, 4, and 5 [4], [5], [6], [7], [8], [9]The combined contribution of CCL-2, 3, 4, and 5 is responsible for the vast functionality of the macrophage phenotypes in response to changing environmental stimuli [4], [5], [6], [7], [8]This dataset represents the observed relationship between injectable insulin use, circulating pro-inflammatory C–C chemokines at breast cancer diagnosis and outcomesReported data has the potential to guide future studies evaluating the impact of insulin-regulated signaling on activation of tumor-associated macrophages in breast cancerOur observations can assist further research clarifying the role of insulin in the regulation of the pro-inflammatory signaling leading to pro-tumorigenic activity in the breast tumor microenvironment…”

“…Their mobilization is a chemotactic response mediated by tumor-derived factors, among which the C–C chemokines CCL-2, 3, 4, and 5 [4], [5], [6], [7], [8], [9]…”

Palmitoylation: a protein S-acylation with implications for breast cancer

“…47 CCR5 also contributes to breast cancer metastasis to bone by mediating the interaction between cancer cells and fibroblasts in the bone cavity. 48 As with most chemokines, CCR5 undergoes palmitoylation at three cysteine residues within its C-terminal region. In immune cells, palmitoylation controls transport of the receptor to the cell surface and its interaction with signaling pathways.…”