from that same paper... 4. The CCL5/CCR5 Axis i

from that same paper...

4. The CCL5/CCR5 Axis in Solid Tumors
A number of solid tumor types express CCL5 and/or CCR5, but only some malignancies were widely studied, thus providing evidence of the involvement of this pair in cancer progression and development. We briefly summarize the role of CCL5/CCR5 in melanoma and gastric, ovarian, cervical, colorectal, and prostate cancer. However, since the most extensive results were obtained in breast cancer, major emphasis is given to this malignancy.

4.1. Breast Cancer
CCL5, while being minimally expressed by normal breast epithelial duct cells, is highly expressed by breast tumor cells at primary tumor sites, regional lymph nodes, and metastatic sites, indicating that CCL5 expression is acquired in the course of malignant transformation [18] and that CCL5 plays a role in breast cancer development and/or progression. Increased positivity and expression levels of CCL5 by breast tumor cells are significantly associated with [57] disease progression, relapse, and/or metastasis, compared to patients in remission [58, 59]. In this tumor the major source of CCL5 is the tumor cells [57]; however, CCL5 is also expressed by infiltrating leukocytes and mesenchymal stem cells (MSCs) of the tumor microenvironment [15, 57, 60]. CCL5 is also present in interstitial fluids perfusing the tumor, in pleural effusions, and in serum [18].

A functional CCR5 receptor is expressed by a subpopulation of human breast cancer cell lines and displays a functional response to CCL5. In addition, oncogene transformation induces CCR5 expression, and the subpopulation of cells that express a functional CCR5 also displays increased cell migration [61] and invasiveness [62]. A microarray analysis on 2,254 human breast cancer specimens found increased expression of CCL5 and its receptor CCR5, but not CCR3, in the basal and HER-2 genetic subtypes [62]. In contrast, when a similar analysis was performed in nonneoplastic breast samples, no correlation between CCL5 and CCR5 expression levels was found, indicating that CCL5/CCR5 signaling may be preferentially activated during the development of specific breast cancer subtypes [62]. CCL5 expression is strongly associated with the progression of breast cancer, particularly the triple-negative breast cancer (TNBC), and may represent an immunotherapeutic target in the TNBC [63].

Hypoxia is a major selective factor that promotes the growth of tumors with a diminished susceptibility to radiation and chemotherapy and is associated with cancer progression, cancer metastasis, and thus poor prognosis. Hypoxia induces a strong increase of both CCL5 and CCR5 expressions by breast cancer cells [64]. Under this experimental condition CCL5 stimulates cell migration rather than cell proliferation and neutralization of CCL5 inhibits the hypoxia-induced migration of cancer cells. Similarly, overexpression of CCR5 increases cell migration, and knockdown of CCR5 attenuates hypoxia-mediated cell migration. Hypoxia-inducible factor-1 (HIF-1) is involved in CCR5 and CCL5 regulation under hypoxia and HIF-1 mRNA levels are highly correlated with CCR5 mRNA and CCL5 mRNA levels in clinical samples [64].