The chemokine RANTES is secreted by human melanoma cells and is associated with enhanced tumour formation in nude mice

Abstract

Modulation of tumour cell growth by tumour-infiltrating leucocytes is of high importance for the biological behaviour of malignant neoplasms. In melanoma, tumour-associated macrophages (TAM) and tumour-infiltrating lymphocytes (TIL) are of particular interest as inhibitors or enhancers of cell growth. Recruitment of leucocytes from the peripheral blood into the tumour site is mediated predominantly by chemotaxins, particularly by the group of chemokines. The aim of this study was to identify peptides released by human melanoma cells with monocyte chemotactic properties. To assure the presence of biologically active mediators, biochemical purification and biological characterization of peptides was based on a detection system dependent on bioactive, monocyte chemotactic activity in vitro. Cell culture supernatants of melanoma cells were fractioned by heparin–sepharose followed by preparative reversed-phase HPLC steps to enrich monocyte chemotactic activity in one single band on a sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) gel. These purified fractions were shown to react with RANTES-specific antibodies in an enzyme-linked immunosorbent assay (ELISA) as well as in Western blot analysis. Amino acid sequencing of the N-terminal protein fragment confirmed 100% homology to the RANTES protein. Further analysis showed that four out of eight melanoma cell lines constitutively expressed and secreted the β-chemokine RANTES as detected by ELISA. The amount of RANTES protein secreted (up to 50 ng ml −1 ) was about 5–50 times higher than interleukin 8 (IL-8), determined in the same supernatant samples. Tumour necrosis factor α (TNF-α), not, however, IL-2, interferon-γ (IFN-γ), or α-melanocyte-stimulating hormone (α-MSH) was able to up-regulate RANTES and interleukin 8 secretion. Furthermore, higher levels of RANTES secretion in vitro were associated with increased tumour formation upon S . C . injection of six human melanoma cell lines in nude mice. Our data provide evidence that a subset of melanoma cells express mRNA and secrete RANTES protein which may be partly responsible for the recruitment of monocytes, T-cells and dendritic cells into the tumours. However, transplantation experiments in nude mice suggest that effects of RANTES may also benefit tumour progression. Further studies are needed to dissect the underlying mechanisms. © 1999 Cancer Research Campaign

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

“…Invasive melanoma is highly resistant to standard forms of cancer therapy (for a review, see Ueda and Richmond, 2006). Based on the fact that several NF-kB-regulated chemokines are constitutively expressed in human melanoma (Mrowietz et al, 1999;Singh et al, 1999;Ueda and Richmond, 2006), it has been proposed that NF-kB plays an important role in melanoma. The role for these chemokines is thought to be at the level of enhancement of growth and survival through autocrine and paracrine mechanisms.…”

CCL5 as a potential immunotherapeutic target in triple-negative breast cancer

“…70 There is evidence that inflammatory chemokines including CCL5 expressed by prostate cells may act directly on the growth and survival of hormone-driven prostate cancer cells. 75 In a Japanese study, it was found that serum CCL5 concentration was significantly elevated in the ovarian cancer patients compared to the benign ovarian cyst patients as controls correlating with the stage of disease and the extent of residual tumor mass.…”

“…A number of other cancer types have been shown to express CCL5, [70][71][72][73][74] induce inflammatory cell migration into the tumor site 71,73,74 and enhance tumor growth. 70 There is evidence that inflammatory chemokines including CCL5 expressed by prostate cells may act directly on the growth and survival of hormone-driven prostate cancer cells.…”

STAT3-RANTES Autocrine Signaling Is Essential for Tamoxifen Resistance in Human Breast Cancer Cells

“…In terms of breast cancer, a number of studies have suggested that RANTES is associated with breast malignancy. In patients with breast cancer, advanced disease, early relapse, and poor prognosis are significantly correlated with elevated RANTES expression levels in biopsy specimens and serum (26)(27)(28). Therefore, the precise role of RANTES signaling in breast cancer should be clarified.…”