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Review
. 2021 Dec:77:83-98.
doi: 10.1016/j.semcancer.2020.12.024. Epub 2021 Jan 18.

Exploring the clinical value of tumor microenvironment in platinum-resistant ovarian cancer

Affiliations
Review

Exploring the clinical value of tumor microenvironment in platinum-resistant ovarian cancer

Alia Ghoneum et al. Semin Cancer Biol. 2021 Dec.

Abstract

Platinum resistance in epithelial ovarian cancer (OvCa) is rising at an alarming rate, with recurrence of chemo-resistant high grade serous OvCa (HGSC) in roughly 75 % of all patients. Additionally, HGSC has an abysmal five-year survival rate, standing at 39 % and 17 % for FIGO stages III and IV, respectively. Herein we review the crucial cellular interactions between HGSC cells and the cellular and non-cellular components of the unique peritoneal tumor microenvironment (TME). We highlight the role of the extracellular matrix (ECM), ascitic fluid as well as the mesothelial cells, tumor associated macrophages, neutrophils, adipocytes and fibroblasts in platinum-resistance. Moreover, we underscore the importance of other immune-cell players in conferring resistance, including natural killer cells, myeloid-derived suppressive cells (MDSCs) and T-regulatory cells. We show the clinical relevance of the key platinum-resistant markers and their correlation with the major pathways perturbed in OvCa. In parallel, we discuss the effect of immunotherapies in re-sensitizing platinum-resistant patients to platinum-based drugs. Through detailed analysis of platinum-resistance in HGSC, we hope to advance the development of more effective therapy options for this aggressive disease.

Keywords: Ascitic fluid; Cisplatin-resistance; OvCa; TME.

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Conflict of interest statement

Conflict of interest: none

Figures

Figure 1:
Figure 1:. Schematic illustration of the cell(s) of origin of ovarian cancer as well as stromal cells, ECM components, and immune Cells Involved in OvCa platinum-resistance.
OvCa cells originate from the ovarian surface epithelium or the surface epithelium of the Fallpian tubes. HGSC: high grade serous ovarian cancer; LGSC: low grade serous cancer; CIC: carcinoma in situ; CCC: clear cell carcinoma; EC: endometroid cancer; ECM: extracellular matrix.
Figure 2:
Figure 2:. Association between cisplatin uptake and export transporters, and catabolic enzyme and patients’ survival.
Kaplan Meier’s curves showing the association between the expression of cisplatin-uptake transporter, SLC31A1, A-E, cisplatin-efflux transporter, ATP7A, B-F, and cisplatin-inactivating enzyme, GCS, C-G, and overall patients survival (OS) and progression-free survival (PFS), respectively in platinum-treated patients with HGSC stages 2+3+4. Tables in D-H indicate the values used in the calculation of OS and PFS, respectively. Significance was deemed at *p<0.05. Graphs were generated from KM Plot (https://www.kmplot.com) [244] with JetSet probe set selected.
Figure 3:
Figure 3:. Schematic illustration of the interconnected activated signaling pathways implicated in disease progression and platinum resistance.
Endothelin-1 (ET1); prostaglandin E2 (PGE2); β/α-chemokine (C-C/CXC); G-protein coupled receptor (GPCR); transforming growth factor beta (TGFβ); transforming growth factor beta Receptor (TGFβR); epidermal growth factor (EGF); vascular endothelial growth factor (VEGF); fibroblast growth factor (FGF); receptor tyrosine kinase (RTK); interleukin 6 (IL-6); interleukin 6 receptor (IL-6R); extracellular matrix (ECM); Ras/mitogen-activated protein kinase(RAS/MAPK); transforming growth factor beta/suppressor of mothers against decapentaplegic (TGFβ/SMAD); Janus kinase/signal transducer and activator of transcription (JAK/STAT); phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR); ETS Like-1 (ELK1) nuclear factor kappa B (NFκB); activator protein 1 (AP-1); signal transducer and activator of transcription 3 (STAT3); T-cell specific transcription factor/lymphoid enhancer binding Factor (TCF/LEF); twist-related protein 1 (TWIST); zinc finger protein SNAI1 (SNAIL); zinc finger protein SNAI1 (SLUG); epithelial to mesenchymal transition (EMT).
Figure 4:
Figure 4:. Correlation of RAF1/ ERK1/2 pathway with survival of platinum-treated HGSC patients.
A-C. Kaplan Meier’s curves showing the association between RAF1/MAPK pathway and overall survival (OS) and progression-free survival (PFS), respectively of platinum-treated patients with HGSC stages 2+3+4. Tables in B-D indicate the values used in the calculation of OS and PFS, respectively. Significance was deemed at *p<0.05. Graphs were generated from KM Plot (https://www.kmplot.com) [244] with JetSet probe set selected.
Figure 5:
Figure 5:. Correlation of PI3K/AKT/MTOR pathway with survival of platinum-treated HGSC patients.
Kaplan Meier’s curves showing the association between PI3K/AKT/MTOR pathway and overall survival (OS) and progression-free survival (PFS), respectively of platinum-treated patients with HGSC stages 2+3+4. Tables in B-D indicate the values used in the calculation of OS and PFS, respectively. Significance was deemed at *p<0.05. Graphs were generated from KM Plot (https://www.kmplot.com) [244] with JetSet probe set selected.
Figure 6:
Figure 6:. Correlation of JAK/STAT pathway with survival of platinum-treated HGSC patients.
Kaplan Meier’s curves showing the association between JAK/STAT pathway and overall survival (OS) and progression-free survival (PFS), respectively of platinum-treated patients with HGSC stages 2+3+4. Tables in B-D indicate the values used in the calculation of OS and PFS, respectively. Significance was deemed at *p<0.05. Graphs were generated from KM Plot (https://www.kmplot.com) [244] with JetSet probe set selected.
Figure 7:
Figure 7:. Correlation of TGFβ/TGFβRs/SMAD pathway with survival of platinum-treated HGSC patients.
Kaplan Meier’s curves showing the association between TGFβ/TGFβRs/SMAD pathway and overall survival (OS) and progression-free survival (PFS), respectively of platinum-treated patients with HGSC stages 2+3+4. Tables in B-D indicate the values used in the calculation of OS and PFS, respectively. Significance was deemed at *p<0.05. Graphs were generated from KM Plot (https://www.kmplot.com) [244] with JetSet probe set selected.

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