TIMP-1 Is Overexpressed and Secreted by Platinum Resistant Epithelial Ovarian Cancer Cells

Abstract

Epithelial Ovarian Cancer (EOC) is the most lethal gynecological cancer in developed countries, and the development of new strategies to overcome chemoresistance is an awaited clinical need. Angiogenesis, the development of new blood vessels from pre-existing vasculature, has been validated as a therapeutic target in this tumor type. The aim of this study is to verify if EOC cells with acquired resistance to platinum (PT) treatment display an altered angiogenic potential. Using a proteomic approach, we identified the tissue inhibitor of metalloproteinases 1 (TIMP-1) as the only secreted factor whose expression was up-regulated in PT-resistant TOV-112D and OVSAHO EOC cells used as study models. We report that TIMP-1 acts as a double-edged sword in the EOC microenvironment, directly affecting the response to PT treatment on tumor cells and indirectly altering migration and proliferation of endothelial cells. Interestingly, we found that high TIMP-1 levels in stage III-IV EOC patients associate with decreased overall survival, especially if they were treated with PT or bevacizumab. Taken together, these results pinpoint TIMP-1 as a key molecule involved in the regulation of EOC PT-resistance and progression disclosing the possibility that it could be used as a new biomarker of PT-resistance and/or therapeutic target.

DEAD-Box Helicase 4 (Ddx4)+ Stem Cells Sustain Tumor Progression in Non-Serous Ovarian Cancers

“…In particular, upregulated DEGs included SIRT1 , which is involved in stemness [ 28 ] and chemoresistance [ 29 ], SNAIL2, which participates in EMT and collagen remodeling [ 30 , 31 ], and SIRT2 , CTGF , IL-11 and MMP13 , involved in cell migration, invasiveness as well as resistance to platinum and paclitaxel [ 32 , 33 , 34 , 35 , 36 ]. Other upregulated DEGs, such as MCM-6 , TGFB-1 , HMGA2 and FOXM1 , are involved in similar cancer-related processes [ 37 , 38 , 39 , 40 , 41 , 42 ], while downregulated DEGs, such as LOX and TIMP-1 (which are associated with poor cancer prognosis [ 43 , 44 , 45 ]), were observed in A2780 co-cultured with both A1 and A2 derived ML-Ddx4 + cells. Among these gene expression alterations, only ADGRL2 and PES1 upregulation were observed in A2780 cells conditioned with control ML-Ddx4 + cells, in a similar fashion to what emerged from the A1-related co-culture.…”

HSP90 identified by a proteomic approach as druggable target to reverse platinum resistance in ovarian cancer

“…CDDP‐resistant cancer cells (referred as Pt‐res cells) were generated as previously described and include pooled resistant populations (pool) and individual clones, as indicated in the text [6–8]. Primary cells (OV102, OV202, OV199, OV200) were established from ascites of EOC patients, collected by the CRO‐Aviano National Cancer Institute Institutional Biobank with a written informed consent from patients.…”

“…CDDP-resistant cancer cells (referred as Pt-res cells) were generated as previously described and include pooled resistant populations (pool) and individual clones, as indicated in the text [6][7][8].…”

“…To investigate the mechanism by which cells acquire platinum-resistance, we took advantage of 2-D DIGE followed by LC-MS/MS to compare the protein expression profile of the three CDDP-resistant cells (TOV-112D Pt-res pool, OVSAHO Pt-res pool and MDAH-2774 Ptres pool) that we have previously established and characterized [6][7][8]. Biological replicates of parental cells or pooled resistant populations (two different pools for each Pt-res cell line) were analyzed by 2-D DIGE proteomic approach performed as previously described [15].…”

“…On this regard, we previously generated and characterized three cisplatin (CDDP)-resistant isogenic high grade EOC cell lines (TOV-112D Pt-res, MDAH-2774 Pt-res and OVSAHO Pt-res) from their parental counterparts [6][7][8]. Since gene expression profiling failed to identify signaling pathways commonly altered in Pt-resistant (Pt-res) cells [6], we took advantage of a proteomic approach to investigate the possible mechanisms by which cells acquire CDDP-resistance.…”