CCR5 Receptor Antagonists Block Metastasis to Bone of v-Src Oncogene–Transformed Metastatic Prostate Cancer Cell Lines

Sicoli, Daniela; Jiao, Xuanmao; Ju, Xiaoming; Velázquez, Marco Antonio Velasco; Ertel, Adam; Addya, Sankar; Li, Zhiping; Andò, Sebastiano; Fatatis, Alessandro; Paudyal, Bishnuhari; Cristofanilli, Massimo; Thakur, Mathew L.; Lisanti, Michael P.; Pestell, Richard G.

doi:10.1158/0008-5472.can-14-0612

Cited by 67 publications

(95 citation statements)

References 39 publications

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“…Stimulation of cancer cells with recombinant CCL5, IL-6, or CXCL10 was able to induce glycogen mobilization. Several studies have established a role for CCL5 in the promotion of metastasis (; Mitra et al, 2012; Sicoli et al, 2014) and while CCL5 secretion was not p38-dependent in our study, CCL5 still plays a role in CAF-mediated glycogen mobilization. It is likely that the unique combination of chemo/cytokines produced by CAFs is required for full stimulation of glycogen mobilization and subsequent metastasis.…”

Section: Discussioncontrasting

confidence: 44%

Fibroblasts Mobilize Tumor Cell Glycogen to Promote Proliferation and Metastasis

et al. 2019

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Successful metastasis requires the co-evolution of stromal and cancer cells. We used stable isotope labeling of amino acids in cell culture coupled with quantitative, label-free phosphoproteomics to study the bidirectional signaling in ovarian cancer cells and human-derived, cancer-associated fibroblasts (CAFs) after co-culture. In cancer cells, the interaction with CAFs supported glycogenolysis under normoxic conditions and induced phosphorylation and activation of phosphoglucomutase 1, an enzyme involved in glycogen metabolism. Glycogen was funneled into glycolysis, leading to increased proliferation, invasion, and metastasis of cancer cells co-cultured with human CAFs. Glycogen mobilization in cancer cells was dependent on p38α MAPK activation in CAFs. In vivo, deletion of p38α in CAFs and glycogen phosphorylase inhibition in cancer cells reduced metastasis, suggesting that glycogen is an energy source used by cancer cells to facilitate metastatic tumor growth.

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Section: Discussioncontrasting

confidence: 44%

Fibroblasts Mobilize Tumor Cell Glycogen to Promote Proliferation and Metastasis

et al. 2019

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“…Several independent groups have observed that CCR5 was expressed by some types of cancer cells including breast [31], prostate [32], and gastric cancer [33]. Furthermore, in these studies, maraviroc directly inhibited the in vivo invasiveness of these cancer cells and reduced subsequent tumor progression.…”

Section: Discussionmentioning

confidence: 99%

Blockade of the chemokine receptor, CCR5, reduces the growth of orthotopically injected colon cancer cells via limiting cancerassociated fibroblast accumulation

et al. 2016

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We previously demonstrated that cancer-associated fibroblasts (CAFs) accumulate at tumor sites through the interaction between a chemokine, CCL3, and its receptor, CCR5, in the late phase of colitis-associated colon carcinogenesis. Here we examined the effect of a CCR5 antagonist, maraviroc, on tumor growth arising from the orthotopic injection of mouse or human colon cancer cell lines into the cecal wall by focusing on CAFs. Orthotopic injection of either cell line caused tumor formation together with leukocyte infiltration and fibroblast accumulation. Concomitant oral administration of maraviroc reduced tumor formation with few effects on leukocyte infiltration. In contrast, maraviroc reduced the intratumor number of α-smooth muscle actin-positive fibroblasts, which express epidermal growth factor, a crucial growth factor for colon cancer cell growth. These observations suggest that maraviroc or other CCR5 antagonists might act as novel anti-CRC drugs to dampen CAFs, an essential cell component for tumor progression.

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“…As CCR5 was identified as a co-receptor mediating the entry of macrophage-tropic HIV [20], the CCR5 antagonist maraviroc has been approved for the treatment of patients with CCR5-tropic HIV infection [48]. However, with increasing evidence for the contribution of CCR5 to cancer progression, maraviroc has been shown to suppress metastasis of breast and prostate cancers in mice [26,28] and to achieve an objective clinical response in patients with advanced-stage metastatic colorectal cancer [29]. Combined with these reports, the current work suggests tumor-promoting effects of CCR5 in a broad range of cancer types, indicating the potential of CCR5 as a common target for cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

High expression of CCR5 in melanoma enhances epithelial–mesenchymal transition and metastasis via TGFβ1

Liu

Wang

et al. 2019

The Journal of Pathology

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Chemokine receptors are highly expressed in various cancers and play crucial roles in tumor progression. However, their expression patterns and functions in melanoma are unclear. The present study aimed to identify the chemokine receptors that play critical roles in melanoma progression and unravel the underlying molecular mechanisms. We found that CCR5 was more abundant in melanoma cells than normal cells and was positively associated with tumor malignancy in clinical patients. Animal experiments suggested that CCR5 deficiency in B16/F10 or A375 cells suppressed primary tumor growth and lung metastasis, whereas CCR5 overexpression in B16/F0 cells enhanced primary tumor growth and lung metastasis. CCR5 played a critical role in proliferation and migration of melanoma cells in vitro. Importantly, CCR5 was required for maintenance of the mesenchymal phenotype of metastatic melanoma cells. Mechanistically, CCR5 positively regulated expression of TGFβ1, which in turn induced epithelial–mesenchymal transition and migration via PI3K/AKT/GSK3β signaling. Collectively, our results establish a critical role of CCR5 expressed by melanoma cells in cancer progression and reveal the novel mechanisms controlling this process, which suggests the prognostic value of CCR5 in melanoma patients and provides novel insights into CCR5‐targeted strategies for melanoma treatment. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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CCR5 Receptor Antagonists Block Metastasis to Bone of v-Src Oncogene–Transformed Metastatic Prostate Cancer Cell Lines

Cited by 67 publications

References 39 publications

Fibroblasts Mobilize Tumor Cell Glycogen to Promote Proliferation and Metastasis

Fibroblasts Mobilize Tumor Cell Glycogen to Promote Proliferation and Metastasis

Blockade of the chemokine receptor, CCR5, reduces the growth of orthotopically injected colon cancer cells via limiting cancerassociated fibroblast accumulation

High expression of CCR5 in melanoma enhances epithelial–mesenchymal transition and metastasis via TGFβ1

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