Can Stemness and Chemoresistance be Therapeutically Targeted via Signaling Pathways in Ovarian Cancer?

Abstract

Ovarian cancer is the most lethal gynecological malignancy. Poor overall survival, particularly for patients with high grade serous (HGS) ovarian cancer, are often attributed to late stage at diagnosis and relapse following chemotherapy. HGS ovarian cancer is a heterogenous disease in that few genes are consistently mutated between patients. Additionally, HGS ovarian cancer is characterized by high genomic instability. For these reasons personalized approaches may be necessary for effective treatment and cure. Understanding the molecular mechanisms that contribute to tumor metastasis and chemoresistance are essential to improve survival rates. One favored model for tumor metastasis and chemoresistance is the cancer stem cell (CSC) model. CSCs are cells with enhanced self-renewal properties that are enriched following chemotherapy. Elimination of this cell population is thought to be a mechanism to increase therapeutic response. Therefore, accurate identification of stem cell populations that are most clinically relevant is necessary. While many CSC identifiers (ALDH, OCT4, CD133, and side population) have been established, it is still not clear which population(s) will be most beneficial to targeted in patients. Therefore, there is a critical need to characterize CSCs with reliable markers and find their weaknesses that will make the CSCs amenable to therapy. Many signaling pathways are implicated for their roles in CSC initiation and maintenance. Therapeutically targeting pathways needed for CSC initiation or maintenance may be an effective way of treating HGS ovarian cancer patients. In conclusion, the prognosis for HGS ovarian cancer may be improved by combining CSC phenotyping with targeted therapies for pathways involved in CSC maintenance.

Rgnef promotes ovarian tumor progression and confers protection from oxidative stress

“…Ovarian cancer tumors growing within the peritoneal space must adapt to environmental stresses from hypoxia, anchorage independence, and metabolic challenges [6]. Peritoneal tumor growth must overcome elevated oxidative stress within cells [7,8].…”

SOX2 upregulates side population cells and enhances their chemoresistant ability by transactivating ABCC1 expression contributing to intrinsic resistance to paclitaxel in melanoma

“…Here, we demonstrate that SOX2 is also sufficient and necessary for the induction of melanoma SP cells. Although not all SP cells have stem cell‐like properties, the SP cells expressing CSCs markers are regarded as a type of CSCs in many tumors including melanoma, and they possess the characteristics of CSCs including self‐renewal, high tumorigenic ability, chemoresistance, and radioresistance . Here, SP cells expressing SOX2, the well‐known CSCs marker, should be a type of melanoma CSCs which should be distinct from the other melanoma CSCs and possess unique characteristics.…”

“…Although not all SP cells have stem cell-like properties, the SP cells expressing CSCs markers are regarded as a type of CSCs in many tumors including melanoma, and they possess the characteristics of CSCs including self-renewal, high tumorigenic ability, chemoresistance, and radioresistance. 10,29,30 Here, SP cells expressing SOX2, the well-known CSCs marker, should be a type of melanoma CSCs which should be distinct from the other melanoma CSCs and possess unique characteristics. Better knowledge of SP cells with SOX2 expression will lead to new insights into melanoma CSCs and the design of more efficient therapy for melanoma treatment.…”

Effects of human umbilical cord mesenchymal stem cells on co‐cultured ovarian carcinoma cells

“…Same with the normal cells, tumor stem cells have lower sensitivity to chemotherapeutic drug, and greater capability to resist chemotherapy and radiotherapy compared with differentiation cells. Therefore, it becomes an important forefront topic around the world to find out a new effective treatment (Roy & Cowden Dahl, ).…”