Genetic and Functional Modifications Associated with Ovarian Cancer Cell Aggregation and Limited Culture Conditions

Abstract

The aggregation of cancer cells provides a survival signal for disseminating cancer cells; however, the underlying molecular mechanisms have yet to be elucidated. Using qPCR gene arrays, this study investigated the changes in cancer-specific genes as well as genes regulating mitochondrial quality control, metabolism, and oxidative stress in response to aggregation and hypoxia in our progressive ovarian cancer models representing slow- and fast-developing ovarian cancer. Aggregation increased the expression of anti-apoptotic, stemness, epithelial-mesenchymal transition (EMT), angiogenic, mitophagic, and reactive oxygen species (ROS) scavenging genes and functions, and decreased proliferation, apoptosis, metabolism, and mitochondrial content genes and functions. The incorporation of stromal vascular cells (SVF) from obese mice into the spheroids increased DNA repair and telomere regulatory genes that may represent a link between obesity and ovarian cancer risk. While glucose had no effect, glutamine was essential for aggregation and supported proliferation of the spheroid. In contrast, low glucose and hypoxic culture conditions delayed adhesion and outgrowth capacity of the spheroids independent of their phenotype, decreased mitochondrial mass and polarity, and induced a shift of mitochondrial dynamics towards mitophagy. However, these conditions did not reduce the appearance of polarized mitochondria at adhesion sites, suggesting that adhesion signals that either reversed mitochondrial fragmentation or induced mitobiogenesis can override the impact of low glucose and oxygen levels. Thus, the plasticity of the spheroids’ phenotype supports viability during dissemination, allows for the adaptation to changing conditions such as oxygen and nutrient availability. This may be critical for the development of an aggressive cancer phenotype and, therefore, could represent druggable targets for clinical interventions.

Obesity modulates the cellular and molecular microenvironment in the peritoneal cavity: implication for ovarian cancer risk

“…Further, the abdominal adipose tissues contain progenitor and stem cells in the stromal vascular fraction that can be recruited to ovarian metastases ( 31 ). We have recently shown that incorporation of the stromal cells supported the survival, adhesion and invasion of non-adherence ovarian cancer cell aggregates via reduced respiration and proliferation, as well as elevated expression of genes that increase senescence, telomere maintenance, and DNA repair ( 22 , 32 ). Whether the HFD changes the stem- and progenitor populations in the abdominal adipose tissues or affects their recruitment to disseminating ovarian metastases needs further investigation.…”

“…The high levels of free fatty acids after ingestion of the HFD may contribute to the high levels of Ccl2 via activation of TLR4 ( 57 ). Ccl2 is also highly expressed in the MOSE-L TIC v cells but is even higher in stromal cells derived from obese adipose tissues, and increased in hypoxic conditions ( 32 ). Thus, the HFD-mediated increase in Ccl2 and its receptor promotes inflammation but also can enhance the autocrine CCL2-CCR2 axis that activates monocytes, macrophages, and NK cells, and promotes macrophage polarization.…”

Mitochondrial Dynamics in Ovarian Cancer: Pathophysiology and Therapeutic Implications

“…Furthermore, nutrient deprivation such as glutamine promotes the malignant biological behavior (e.g., stemness and chemoresistance) of ovarian cancer cells via DRP1-induced mitochondrial fragmentation with enhanced glycolysis [58]. Ovarian cancer cells can reprogram mitochondrial function and localization in response to intracellular energetic demands, the nutrient supply, and a hypoxic environment [34,59,60]. In addition, mitochondrial dynamics contribute to maintaining the regenerative competence of not only cancer cells but also normal cells through the activation of genes that control mitochondrial fusion and fission [39,61] (Figure 1, Stemness).…”