New markers for human ovarian cancer that link platinum resistance to the cancer stem cell phenotype and define new therapeutic combinations and diagnostic tools

Abstract

Background Ovarian cancer is the leading cause of gynecologic cancer-related death, due in part to a late diagnosis and a high rate of recurrence. Primary and acquired platinum resistance is related to a low response probability to subsequent lines of treatment and to a poor survival. Therefore, a comprehensive understanding of the mechanisms that drive platinum resistance is urgently needed. Methods We used bioinformatics analysis of public databases and RT-qPCR to quantitate the relative gene expression profiles of ovarian tumors. Many of the dysregulated genes were cancer stem cell (CSC) factors, and we analyzed its relation to therapeutic resistance in human primary tumors. We also performed clustering and in vitro analyses of therapy cytotoxicity in tumorspheres. Results Using bioinformatics analysis, we identified transcriptional targets that are common endpoints of genetic alterations linked to platinum resistance in ovarian tumors. Most of these genes are grouped into 4 main clusters related to the CSC phenotype, including the DNA damage, Notch and C-KIT/MAPK/MEK pathways. The relative expression of these genes, either alone or in combination, is related to prognosis and provide a connection between platinum resistance and the CSC phenotype. However, the expression of the CSC-related markers was heterogeneous in the resistant tumors, most likely because there were different CSC pools. Furthermore, our in vitro results showed that the inhibition of the CSC-related targets lying at the intersection of the DNA damage, Notch and C-KIT/MAPK/MEK pathways sensitize CSC-enriched tumorspheres to platinum therapies, suggesting a new option for the treatment of patients with platinum-resistant ovarian cancer. Conclusions The current study presents a new approach to target the physiology of resistant ovarian tumor cells through the identification of core biomarkers. We hypothesize that the identified mutations confer platinum resistance by converging to activate a few pathways and to induce the expression of a few common, measurable and targetable essential genes. These pathways include the DNA damage, Notch and C-KIT/MAPK/MEK pathways. Finally, the combined inhibition of one of these pathways with platinum treatment increases the sensitivity of CSC-enriched tumorspheres to low doses of platinum, suggesting a new treatment for ovarian cancer. Electronic supplementary material The online version of this article (10.1186/s13046-019-1245-5) contains supplementary material, which is available to authorized users.

Downregulation of MYPT1 increases tumor resistance in ovarian cancer by targeting the Hippo pathway and increasing the stemness

“…Resistance to antitumoral agents, especially cytotoxicity, has been linked to the presence of CSCs in tumors [42,43]. It is believed that chemotherapy is effective against non-CSC tumor cells but not against CSCs, which are able to initiate new tumor growth after therapy and promote metastasis.…”

The Application of Biomaterials in the Treatment of Platinum‐Resistant Ovarian Cancer

“…This evidence for C‐KIT cross‐talk with NANOG and OCT4 specifically, is supported by earlier studies which revealed that cisplatin treatment enhances the expression of C‐KIT , NANOG and OCT4 in residual ovarian cancer cells in vitro . Furthermore, inhibition of the NOTCH and C‐KIT/MAPK/MEK pathways in vitro re‐sensitized OCa CSC‐enriched tumorshperes to cisplatin and carboplatin . Based on these lines of evidence, the targeting of stemness pathways has therefore been proposed as a strategy to increase the effectiveness of cancer therapies.…”

“…The genes involved in these pathways are often dysregulated in Oca CSC‐LCs, and are usually integrated into three main clusters involving the WNT/ Β‐ CATENIN/NOTCH network, the MEK/MAPK network and the NANOG/SOX2/OCT4/KLF4 network . Interestingly, in Oca patients with platinum‐resistant tumors, these three pathways were found to be interconnected through a fourth pathway involving C‐KIT, STAT3, NOTCH1 and MYC . This evidence for C‐KIT cross‐talk with NANOG and OCT4 specifically, is supported by earlier studies which revealed that cisplatin treatment enhances the expression of C‐KIT , NANOG and OCT4 in residual ovarian cancer cells in vitro .…”

“…CSC‐LCs function rely on their ability to promote the activity of stemness pathways. The genes involved in these pathways are often dysregulated in Oca CSC‐LCs, and are usually integrated into three main clusters involving the WNT/ Β‐ CATENIN/NOTCH network, the MEK/MAPK network and the NANOG/SOX2/OCT4/KLF4 network . Interestingly, in Oca patients with platinum‐resistant tumors, these three pathways were found to be interconnected through a fourth pathway involving C‐KIT, STAT3, NOTCH1 and MYC .…”

Therapeutic Targeting of Signaling Pathways Related to Cancer Stemness

“…CSCs and non-CSCs can also interconvert in dynamic equilibrium. Non-CSCs can acquire CSC properties through de-differentiation (8,(22)(23)(24), and in this process, either genetic or epigenetic alterations, as well as microenvironment may be involved (25)(26)(27)(28). Therefore, the CSCs model should be considered to be bidirectional, switching between stem and mature cells within the tumor (8,(22)(23)(24).…”