Lung adenocarcinoma invasion in TGFβRII-deficient cells is mediated by CCL5/RANTES

Abstract

Recently, we identified a lung adenocarcinoma signature that segregated tumors into three clades distinguished by histological invasiveness. Among the genes differentially expressed was the type II transforming growth factor-b receptor (TGFbRII), which was lower in adenocarcinoma mixed subtype and solid invasive subtype tumors compared with bronchioloalveolar carcinoma. We used a tumor cell invasion system to identify the chemokine CCL5 (RANTES, regulated on activation, normal T-cell expressed and presumably secreted) as a potential downstream mediator of TGF-b signaling important for lung adenocarcinoma invasion. We specifically hypothesized that RANTES is required for lung cancer invasion and progression in TGFbRII-repressed cells. We examined invasion in TGFbRII-deficient cells treated with two inhibitors of RANTES activity, Met-RANTES and a CCR5 receptor-blocking antibody. Both treatments blocked invasion induced by TGFbRII knockdown. In addition, we examined the clinical relevance of the RANTES-CCR5 pathway by establishing an association of RANTES and CCR5 immunostaining with invasion and outcome in human lung adenocarcinoma specimens. Moderate or high expression of both RANTES and CCR5 was associated with an increased risk for death, P ¼ 0.014 and 0.002, respectively. In conclusion, our studies indicate RANTES signaling is required for invasion in TGFbRIIdeficient cells and suggest a role for CCR5 inhibition in lung adenocarcinoma prevention and treatment.

Selectin-mediated activation of endothelial cells induces expression of CCL5 and promotes metastasis through recruitment of monocytes

“…CCL5 was previously associated with the progression of breast cancer in several independent studies, but only a direct effect on tumor cells was examined. 29,30,36,46,47 Accordingly, CCL5 derived from mesenchymal stem cells was found to induce a metastatic phenotype through binding to its receptor CCR5 on tumor cells within the primary tumor that increased metastasis to the lungs. 29 In our model we observed a CCL5-dependent recruitment of monocytes to metastasizing tumor cells, suggesting a function of CCL5 in shaping the metastatic microenvironment rather than directly affecting tumor cells (supplemental Figure 11).…”

“…40 Moreover, previous findings showed that CCL5 was detected in pulmonary stromal fibroblasts of human lung adenocarcinoma specimens. 36 Thus, activated interstitial fibroblast could be Mean Ϯ SEM; n ϭ 3. As positive controls, HMVECs were stimulated with TNF␣ (10 ng/mL) and interferon ␥ (1 ng/mL).…”

“…Due to the known association of CCL5 with cancer progression, 29,30,36 we further evaluated the functionality of CCL5 expression by HMVECs. CCL5 is chemotactic for different subtypes of leukocytes that have been involved in cancer progression including myeloid cells such as monocytes.…”

Overexpression of <i>KLF13</i> and <i>FGFR3</i> in Oral Cancer Cells

“…KLF13 can play the role of an activator, as it does for CCL5 (RAN-TES) [Song et al, 1999], or that of a repressor, as it does for CYP1A1 [Kaczynski et al, 2003]. This is of particular importance, since CCL5 is a chemotactic chemokine in inflammatory cells and is overexpressed in lung cancer, breast cancer, prostate cancer, melanoma, T-cell leukemia, ovarian cancer, and oral cancer [Negus et al, 1997;Robinson et al, 2003;Mori et al, 2004;Vaday et al, 2006;Karnoub et al, 2007;Borczuk et al, 2008;Chuang et al, 2009], and CYP1A1 plays a role in head and neck and lung cancers [Agundez, 2004;Li et al, 2004;Hiyama et al, 2008]. KLF13 is also required for the expression of cyclin D1, which is a known oncogene in OSCC [Nemer and Horb, 2007].…”

Epidermal Smad4 Deletion Results in Aberrant Wound Healing

“…Supporting the last two possibilities, both epidermal and stromal cells showed increased nuclear pSmad2 in Smad4 KO skin ( Figure 6). Moreover, several potential TGF␤ target genes with protumorigenic functions, including CCL5, 19,21,30 CCL20, 22,[31][32][33][34] VEGFA, and MMPs, were elevated in Smad4 KO skin and during wound healing. Some of these molecules (eg, CCL5, CCL20, VEGFA, and MMP14) were further elevated in Smad4 KO SCCs when compared with Smad4 KO wounds, which could be caused by further elevation of TGF␤1 levels or additional oncogenic alterations in Smad4 KO SCCs.…”