Rantes / CCL5 is associated with cancer progression and metastasis. Rantes / CCL5 interactions with CCR5 may favor tumor development in multiple ways: acting as growth factors, stimulating angiogenesis, modulating the extracellular matrix, inducing the recruitment of additional stromal and inflammatory cells, and taking part in immune evasion mechanisms. The Rantes / CCL5 ligand have been detected in some hematological malignancies, lymphomas, and a great number of solid tumors (multiple myeloma (MM), classical Hodgkin lymphoma (cHL), prostate, breast, gastric, colon, and ovarian cancer, and melanoma.) Thus Rantes / CCL5 serves as a crucial drug target in cancer therapy.
The current observations propose two major mechanisms by which Rantes / CCL5 released by tumor cells and their receptors support multiple myeloma progression:
Proposed role of the Rantes / CCL5-CCR5 axis in Hodgkin Lymphoma leading to tumor cell proliferation and microenvironment formation: 1)Rantes / CCL5 produced by classical Hodgkin Lymphoma cells may represent an autocrine growth factor. 2) Rantes / CCL5 secreted by T cells or fibroblasts may represent a paracrine growth factor. 3) CD40L increases Rantes / CCL5 secretion by classical Hodgkin Lymphoma cells and they induce fibroblasts to secrete Rantes / CCL5. Rantes / CCL5 secreted by classical Hodgkin Lymphoma (direct recruitment) or fibroblasts activated by Hodgkin Lymphoma cells (indirect recruitment) may in turn recruit CD4+ T cells, T-reg cells, eosinophils, and mast cells. As a consequence Rantes / CCL5 and the CCR5 ligands secreted by tumor cells or by the surrounding T-cells, macrophages, or fibroblasts may support Hodgkin Lymphoma progression by increasing proliferation and by recruiting cells involved in the microenvironment formation.
Cancer cells stimulate Rantes / CCL5 secretion by MSCs and osteoblasts of the tumor microenvironment and Rantes / CCL5 in turn induces tumor cell migration and promotes invasion and metastasis. Rantes / CCL5 supports breast malignancy by changing the equilibrium between leukocyte infiltrates in tumors, leading to dominance of cells with tumor-promoting rather than tumor killing activities. In fact, Rantes / CCL5 shifts the balance between different leukocyte cell types by increasing the presence of deleterious tumor-associated macrophages (TAMs) that secrete proangiogenic factors, suppress the antitumor response and inhibit the antitumor T-cell activities. Thus Rantes / CCL5 seems to have a crucial role in cancer progression and may represent an important breast cancer therapeutic target with minimal adverse impact.
Rantes / CCL5 and CCR5 are expressed by melanoma cells, primary melanomas, and cutaneous metastasis. Rantes / CCL5 is higher in melanoma cells than in normal melanocytes and is associated with a higher malignancy state and increased tumor formation. Already a previous study by Mellado et al. had shown that CCR5 plays a key role in inducing apoptotic death in tumor infiltrated lymphocytes (TIL) in a Rantes / CCL5-dependent manner: CXCL12 released by melanoma cells induced the expression of Rantes / CCL5 by TIL, which in turn activated their death program. This makes Rantes / CCL5 to be a possible drug target in melanoma therapy.
Gastric cancer cells exploit Rantes / CCL5, not only for their own growth, but also to assist in evasion of the host immune system. Rantes / CCL5 serum levels correlate with the clinical stage and treatment with Rantes / CCL5 promotes tumor growth. Gastric cancer cells stimulate CD4+ T lymphocytes to secrete Rantes / CCL5 and they may also induce Fas-FasL-mediated apoptosis of CD8+ T lymphocytes using Rantes / CCL5. The conclusion is that the Rantes / CCL5-CCR5 axis seems associated with gastric cancer progression due to increased growth and metastasis formation.
Knockdown of Rantes / CCL5 from CT26 mouse colon tumor cells decreases apoptosis of tumor-infiltrating CD8+ T cells and reduces tumor growth in mice. Here, Rantes / CCL5 not only promotes migration of T-reg cells to tumors but also enhances the killing ability on CD8+T cells.This augmented function is associated with the increased release of TGF-?? by T-reg cells. Rantes / CCL5-CCR5 signaling recruits T-regs which in turn eliminate CD8+ T cells, thereby defining a novel mechanism of immune escape in colorectal cancer and pointing to the potential value of Rantes / CCL5 as a drug target
The Rantes / CCL5-CCR5 axis is involved also in prostate cancer progression: both are expressed in human prostate cancer cell lines, primary cultures of prostatic adenocarcinoma cells, and prostate cancer tissues. Rantes / CCL5 stimulates prostate cancer cell proliferation and invasion and both are inhibited by the CCR5 antagonist TAK-779. Rantes / CCL5 increases prostate cancer proliferation in synergy with IL-6 and it is also induced by the antibody-mediated aggregation of the prostate specific membrane antigen (PSMA). PSMA is a type-II integral membrane protein capable of activating the NF-??B transcription factor, predominantly localized to the epithelial cells of the prostate gland and whose expression increases several fold in high-grade prostate cancers and in metastatic and in androgen-insensitive prostate carcinoma.
Recently Long et al. demonstrated that Rantes / CCL5 is expressed in ovarian cancer stem cells characterized by the expression of CD133 antigen that identifies a specific subpopulation of human ovarian cancer cell line and ovarian cancer tissue in which migration and invasion are particularly enhanced. In comparison to CD133-negative non-ovarian cancer stem cells, Rantes / CCL5 and its receptors, CCR1, CCR3, and CCR5, are consistently upregulated in CD133-positive cells, and blocking of Rantes / CCL5, CCR1, or CCR3 effectively inhibits the invasive capacity of CSLCs. The enhanced invasiveness is mediated through NF-??B activation along with elevated MMP-9 secretion, suggesting that the autocrine activation of CCR1 and CCR3 by Rantes / CCL5 represents one of the major mechanisms underlying the metastatic property of ovarian cancer cells.
Overall, our current knowledge leads us to suggest the Rantes / CCL5-CCR5 axis as a potential therapeutic target in several cancer diseases. However, bringing this proposal into practical application requires further research to more clearly elucidate the effects of Rantes / CCL5 on cancer progression and the formation of an immunosuppressive microenvironment to insure that such treatments are supported by the appropriate rationale.
Aldinucci D, et al. The inflammatory chemokine Rantes and cancer progression[J]. Mediators of inflammation, 2014, 2014.