Adipose Progenitor Cell Secretion of GM-CSF and MMP9 Promotes a Stromal and Immunological Microenvironment That Supports Breast Cancer Progression

Abstract

A cell population with progenitor-like phenotype (CD45-CD34) resident in human white adipose tissue (WAT) is known to promote the progression of local and metastatic breast cancer and angiogenesis. However, the molecular mechanisms of the interaction have not been elucidated. In this study, we identified two proteins that were significantly upregulated in WAT-derived progenitors after coculture with breast cancer: granulocyte macrophage colony-stimulating factor (GM-CSF) and matrix metallopeptidase 9 (MMP9). These proteins were released by WAT progenitors in xenograft and transgenic breast cancer models. GM-CSF was identified as an upstream modulator. Breast cancer-derived GM-CSF induced GM-CSF and MMP9 release from WAT progenitors, and GM-CSF knockdown in breast cancer cells neutralized the protumorigenic activity of WAT progenitors in preclinical models. GM-CSF neutralization in diet-induced obese mice significantly reduced immunosuppression, intratumor vascularization, and local and metastatic breast cancer progression. Similarly, MMP9 inhibition reduced neoplastic angiogenesis and significantly decreased local and metastatic tumor growth. Combined GM-CSF neutralization and MMP9 inhibition synergistically reduced angiogenesis and tumor progression. High-dose metformin inhibited GM-CSF and MMP9 release from WAT progenitors in and xenograft models. In obese syngeneic mice, metformin treatment mimicked the effects observed with GM-CSF neutralization and MMP9 inhibition, suggesting these proteins as new targets for metformin. These findings support the hypothesis that GM-CSF and MMP9 promote the protumorigenic effect of WAT progenitors on local and metastatic breast cancer..

Retinoprotection by BGP-15, a Hydroximic Acid Derivative, in a Type II Diabetic Rat Model Compared to Glibenclamide, Metformin, and Pioglitazone

“…Our result regarding the MMP9-lowering effect of glibenclamide in the diabetic eye is a novelty. Metformin was proved to reduce MMP9 synthesis in many different pathologies e.g., in adipocytes in insulin resistant diabetes [48], in breast cancer [49], in spinal cord injury [50], etc., but so far no scientific article demonstrated this effect in eye of diabetic animals as in this present study. The same applies to pioglitazone: pioglitazone was demonstrated to lower MMP9 levels in e.g., murine peritoneal macrophages [51], in lung [52] and breast [53] cancer cells, as well as in serum of atherosclerotic rabbit model [54].…”

Predictive and prognostic value of Matrix metalloproteinase (MMP) - 9 in neoadjuvant chemotherapy for triple-negative breast cancer patients

“…Among all MMPs, MMP-9 has been the most commonly studied. A recent study stated that GM-CSF and MMP-9 promote the protumorigenic effect of WAT progenitors on local and metastatic breast cancer [ 20 ]. Some other study noted that MMP-9 could be regulated by DNA methylation in breast cancer, which might resulted in the first step of metastasis through extracellular matrix degradation [ 21 ].…”

Bone marrow niche-derived extracellular matrix-degrading enzymes influence the progression of B-cell acute lymphoblastic leukemia

“…Heparanase, cleaving heparan sulfate, and MMPs, which belong to the family of zinc-dependent endopeptidases, are involved in remodeling of the ECM. In cancer, MMPs may be produced by tumor [16] or stromal cells [17], where they degrade the ECM facilitating cancer progression. One such MMP is matrix metalloproteinase-9 (MMP-9) or gelatinase B [14], produced by macrophages, neutrophils [18], fibroblasts [19], MSC [20,21], and other cells.…”