GM‐CSF enhances tumor invasion by elevated MMP‐2, ‐9, and ‐26 expression

Abstract

Granulocyte–macrophage colony-stimulating factor (GM-CSF) promotes tumor progression in different tumor models in an autocrine and paracrine manner. However, at the same time GM-CSF is used in cancer therapies to ameliorate neutropenia. We have previously shown in GM-CSF and G-CSF expressing or negative skin or head and neck squamous cell carcinoma that GM-CSF expression is associated with a highly angiogenic and invasive tumor phenotype. To determine the functional contribution of GM-CSF to tumor invasion, we stably transfected a GM-CSF negative colon adenocarcinoma cell line HT-29 with GM-CSF or treated the same cell line with exogenous GM-CSF. While GM-CSF overexpression and treatment reduced tumor cell proliferation and tumor growth in vitro and in vivo, respectively, it contributed to tumor progression. Together with an enhanced migratory capacity in vitro, we observed a striking increase in tumor cell invasion into the surrounding tissue concomitant with the induction of an activated tumor stroma in GM-CSF overexpressing or GM-CSF treated tumors. In a complex 3D in vitro model, enhanced GM-CSF expression was associated with a discontinued basement membrane deposition that might be mediated by the increased expression and activation of MMP-2, -9, and -26. Treatment with GM-CSF blocking antibodies reversed this effect. The increased presence and activity of these tumor cell derived proteases was confirmed in vivo. Here, expression of MMP-26 protein was predominantly located in pre- and early-invasive areas suggesting MMP-26 expression as an early event in promoting GM-CSF dependent tumor invasion.

Allicin inhibits the invasion of lung adenocarcinoma cells by altering tissue inhibitor of metalloproteinase/matrix metalloproteinase balance via reducing the activity of phosphoinositide 3-kinase/AKT signaling

“…Normally, TIMPs specifically combine with MMPs and keep their activity in a dynamic balance. However, once this balance is broken, invasion and metastasis of cancer cells is induced (6)(7)(8)(9). The imbalance between TIMPs and MMPs has been recognized as the main mechanism for promoting the invasive processes of lung cancer.…”

“…3). Previous studies indicated that the expression of MMPs was regulated by their endogenous tissue inhibitors (TIMPs) (7)(8)(9). Thus, the expression levels of TIMP-1 and TIMP-2 in H1299 cells were examined by RT-qPCR and western blot analysis following treatment with 0, 5.0, 7.5 and 10.0 µM of allicin for 48 h. It was identified that allicin upregulated the RNA and protein levels of TIMP-1 and TIMP-2 in H1299 cells in a concentration-dependent manner (Fig.…”

“…Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, play an important role in the invasion process of numerous malignant tumors by degrading the basement membrane and extracellular matrix (ECM) (6)(7)(8). Previous studies have suggested that MMP-2 and MMP-9 are associated with invasion in lung cancer (4,5).…”

Dual role of macrophages in the response of C26 colon carcinoma cells to 5-fluorouracil administration

“…However, in the presence of macrophages, 5-FU treatment moderately to very strongly reduced the production of the majority of the pro-angiogenic (VEGF, eotaxin, thrombopoietin, bFGF) and pro-inflammatory (M-CSF, IL-1α, IL-1β, IL-12p40, MCP-1, G-CSF, GM-CSF, IL-6, FasL) proteins compared to their production in the untreated cell co-culture (Table I). The significant inhibition of these proteins could account for the high 5-FU cytotoxicity induced through the suppression of NF-κB since the aforementioned proteins have also been associated with the proliferation, survival and metastasis of cancer cells (7,8,10,31,32). Furthermore, NF-κB signaling has been described as the main mechanism for maintaining the pro-tumor phenotype of TAMs (33,34).…”

Presence of mast cells and the expression of metalloproteinase 9 in the gingiva of ovariectomized rats with periodontal disease

“…12 The MMPs have been found in cases of inflammatory periodontal disease and are related to the progress of the periodontal disease. 3 Some authors have investigated the role of the MMPs 2 13,14 and 9 [13][14][15] in the progress of periodontitis, 16 but the participation of those enzymes in the process has not been totally established.…”