Rantes / CCL5: Cancer Drug Target in Cytokines & Growth factors

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.

Rantes / CCL5 as multiple myeloma Drug Target

The current observations propose two major mechanisms by which Rantes / CCL5 released by tumor cells and their receptors support multiple myeloma progression:

Rantes / CCL5 as Hodgkin Lymphoma Drug Target

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.

Rantes / CCL5 as Breast Cancer Drug Target

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 as Melanoma Drug Target

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.

Rantes / CCL5 as Gastric Cancer Drug Target

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.

Rantes / CCL5 as Colon Cancer Drug Target

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

Rantes / CCL5 as Prostate Cancer 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.

Rantes / CCL5 as Ovarian Cancer Drug Target

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.

Rantes / CCL5 as Cancer Drug Target: Conclusion

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.

Rantes / CCL5: Cancer Drug Target in Cytokines & Growth Factors Reference

Aldinucci D, et al. The inflammatory chemokine Rantes and cancer progression[J]. Mediators of inflammation, 2014, 2014.