TIMP-1 Promotes Accumulation of Cancer Associated Fibroblasts and Cancer Progression

Abstract

Treatment options for late stage prostate and colon cancer are limited and there is an urgent need to develop more effective and targeted novel therapies, which starts with identification and validation of novel therapeutic targets. Recent clinical studies have demonstrated that tissue inhibitor matrix metalloproteinase-1 (TIMP-1) levels are elevated in cancer patient plasma and elevated TIMP-1 levels are associated with worse clinical outcomes. However, it is unknown whether TIMP-1 serves merely as a biomarker of cancer progression or has a functional role in promoting cancer progression and can serve as a cancer therapeutic target, which is the main objective of this study. Here, we show that stroma of human prostate and colon cancer express higher levels of TIMP-1 compared to their normal counterparts and increased expression of TIMP-1 promotes in vivo growth of both cancer types. We demonstrate for the first time that increased TIMP-1 expression stimulates accumulation of cancer associated fibroblasts (CAFs) within prostate and colon cancer tissues and that TIMP-1 enhances prostate CAF proliferation and migration in vitro and promotes ERK1/2 kinase activation in these CAF cells. Our results establish the novel promotive effects of TIMP-1 on cancer progression and on accumulation of CAFs that in turn provides a pro-tumor microenvironment. Together, these results establish the potential of TIMP-1 as a novel target for cancer therapy and the mechanism underlying the pro-tumor activity of TIMP-1.

Rapamycin increases CCN2 expression of lung fibroblasts via phosphoinositide 3-kinase

“…23 Also, another profibrotic mediator, TIMP-1, was shown to promote the migration of cancer-associated fibroblasts (CAFs). 24 So, we hypothesized that whether rapamycin, via modulating CCN2 and TIMP-1 expression, affects HLFs migration. We found although CCN2 and TIMP-1 expression was upregulated by rapamycin, the migration of fibroblast was unchanged ( Figure 10).…”

“…23,24 ELISA found that rapamycin itself remarkably increased TIMP-1 protein level in culture media (Figure 10e). However, wound healing study showed that the migratory capacity of F-HLFs was not changed by rapamycin (Figure 10a and b).…”

“…To investigate modulatory effects of rapamycin (Sigma, San Francisco, CA, USA) on cell behavior, normal or fibrotic HLFs (N-/F-HLFs) were incubated for different periods of time (1,6,12,24, and 48 h) with rapamycin (5 ng/ml) in the absence or presence of transforming growth factor (TGF)-β1 (10 ng/ml, BD, San Diego, CA, USA). To study the modulatory mechanisms of rapamycin on HLFs, TGF-β type I receptor (TβRI)-and phosphoinositide 3-kinase (PI3K)-specific antagonist (SB431542 and LY294002; 5 and15 μM; Biotrend, Cologne, Germany) was used.…”

Lysyl Oxidase (LOX) Transcriptionally Regulates SNAI2 Expression and TIMP4 Secretion in Human Cancers

“…The significant positive correlation between LOX-SNAI2 and the percentage of stromal cells in tumor further support the role of this axis in cancer invasion and metastasis. Accumulation of cancer-associated fibroblasts induced by TIMP1 has been shown in colon and prostate cancer; therefore, it is possible that TIMP4 secreted by tumors overexpressing LOX and SNAI2 may promote stromal cells infiltration in aggressive tumors (48).…”

LNA aptamer based multi-modal, Fe 3 O 4 -saturated lactoferrin (Fe 3 O 4 -bLf) nanocarriers for triple positive (EpCAM, CD133, CD44) colon tumor targeting and NIR, MRI and CT imaging

“…Complete inhibition of TIMP-4 was also observed. The TIMP levels are generally reported in association with cancer progression [46]. The findings from the cytokine array analysis were also quite interesting as M A N U S C R I P T…”