Breast tumor-associated osteoblast-derived CXCL5 increases cancer progression by ERK/MSK1/Elk-1/Snail signaling pathway

Abstract

The skeleton is the most common metastatic site for breast cancer, with bone metastasis causing pain as well as risk of pathological fractures. Interaction between tumors and the bone microenvironment creates a vicious cycle that accelerates both bone destruction and cancer progression. This study is the first to analyze the soluble factors secreted by breast tumor-associated osteoblasts (TAOBs), which are responsible for promoting cancer progression. The addition of CXCL5 (chemokine (C-X-C motif) ligand 5), present in large amounts in TAOB-condition medium (TAOB-CM), mimicked the inductive effect of TAOB-CM on breast cancer epithelial-mesenchymal transition, migration and invasion. In contrast, inhibition of CXCL5 in OBs decreased TAOB-mediated cancer progression. Inducement of MCF-7 and MDA-MB-231 cancer progression by TAOB-derived CXCL5 is associated with increased Raf/MEK/ERK activation, and mitogen- and stress-activated protein kinase 1 (MSK1) and Elk-1 phosphorylation, as well as Snail upregulation. Activation of Elk-1 facilitates recruitment of phosphorylated MSK1, which in turn enhances histone H3 acetylation and phosphorylation (serine 10) of Snail promoter, resulting in Snail enhancement and E-cadherin downregulation. Moreover, mice treated with anti-CXCL5 antibodies showed decreased metastasis of 4T1 breast cancer cells. Our study suggests that inhibition of CXCL5-mediated ERK/Snail signaling is an attractive therapeutic target for treating metastases in breast cancer patients.

Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone

“…Other studies have identified CXCL5 as a predictor for bone-metastatic prostate cancer (52), and in a breast cancer metastatic model it was shown that this cytokine is a factor secreted by tumor-associated osteoblasts to function as an inducer of epithelialto-mesenchymal transition and metastasis (53). Furthermore, in a model of rhabdomyosarcoma, it was demonstrated that antibody-mediated neutralization of CXCR2 (a receptor for CXCL5) enhanced anti-PD1 effectiveness by preventing the tumor infiltration of the CD11b + Ly6G hi suppressor cells (54).…”

Cell Cycle M-Phase Genes Are Highly Upregulated in Anaplastic Thyroid Carcinoma

“…It is likely that the CXCL5 upregulation may reflect inclusion of macrophage RNA in the analyses, but it is also possible that CXCL5 also may play a role in ATC tumor biology. CXCL5 has recently been implicated in mediating cell proliferation, migration and invasion in colorectal cancer and is associated with metastasis and worse prognosis in gastric and breast cancer (36,37). Another novel, ATC-specific overexpressed gene encodes the disks large-associated protein 5 (DLGAP5), a component of the kinetochore responsible for stabilizing microtubules and the spindle apparatus.…”

Inflammation and skeletal metastasis

“…169 Metastatic cancer cells secrete factors that induce proinflammatory cytokines/chemokines in osteoblasts such as IL-6, IL-8, CCL2 and CXCL5. [170][171][172] One of the factors expressed by cancer cells in response to different stimuli such as TGFb is parathyroid hormone-related protein (PTHrP), which acts in a paracrine manner to induce CCL2, IL-6 and the soluble IL-6 receptor (sIL-6R) in osteoblasts. 159,[173][174][175] A recent study showed that PTHrP induces IL-6 and VEGF-A in osteoblasts to activate CD11b þ /Gr1 þ myeloid cells in the bone marrow and enhance angiogenesis, the expression of matrix remodeling proteases and prostate cancer growth in bone.…”