Abstract
Simple SummaryDuring metastasis, ovarian cancer spheroids move from the original tumor and travel through the abdominal cavity to other sites. During the movement of spheroids, cells are exposed to an environment with little oxygen or glucose, unlike how cells are traditionally cultured. In this study, we used culture conditions relevant to the abdominal cavity to investigate how energy production and fuel sources change as spheroids adhere to a secondary location. Using early time points of adhesion, we show that over time, spheroids change their metabolism as well as fuel sources as they grow out. This suggests that adhesion to another site initiates a metabolic switch that supports outgrowth and successful metastasis. This is important because if we understand how these cancer cells shift from a dormant into a growing state we can identify drug targets that may suppress these signaling pathways leading to the metabolic switch and preventing the ovarian metastases from growing and invading other tissues. This may prolong the life of women with ovarian cancer.Ovarian cancer remains a deadly disease and its recurrence disease is due in part to the presence of disseminating ovarian cancer aggregates not removed by debulking surgery. During dissemination in a dynamic ascitic environment, the spheroid cells’ metabolism is characterized by low respiration and fragmented mitochondria, a metabolic phenotype that may not support secondary outgrowth after adhesion. Here, we investigated how adhesion affects cellular respiration and substrate utilization of spheroids mimicking early stages of secondary metastasis. Using different glucose and oxygen levels, we investigated cellular metabolism at early time points of adherence (24 h and less) comparing slow and fast-developing disease models. We found that adhesion over time showed changes in cellular energy metabolism and substrate utilization, with a switch in the utilization of mostly glutamine to glucose but no changes in fatty acid oxidation. Interestingly, low glucose levels had less of an impact on cellular metabolism than hypoxia. A resilience to culture conditions and the capacity to utilize a broader spectrum of substrates more efficiently distinguished the highly aggressive cells from the cells representing slow-developing disease, suggesting a flexible metabolism contributes to the stem-like properties. These results indicate that adhesion to secondary sites initiates a metabolic switch in the oxidation of substrates that could support outgrowth and successful metastasis.
Highlights
Ovarian cancer is the deadliest gynecological cancer and remains the fifth leading cause of cancer death in women [1] due in part to a late diagnosis after metastasis has occurred [2]
We have shown that the survival of aggregated ovarian cancer cells is associated with a significantly reduced respiration and highly fragmented mitochondrial phenotype leading to a reduced proliferation [8,31]
At 24 h in mouse ovarian surface epithelial (MOSE-L), basal respiration was significantly reduced in low glucose (LG) HO (p < 0.05), and hypoxia increased spare respiratory capacity (HG HO p < 0.001, LG HO p < 0.0001)
Summary
Ovarian cancer is the deadliest gynecological cancer and remains the fifth leading cause of cancer death in women [1] due in part to a late diagnosis after metastasis has occurred [2]. Cells or cell clusters are exfoliated from the original tumor on the ovaries or fallopian tubes [3,4] and aggregate to form multicellular spheroids [5]. The spheroids are spread throughout the peritoneal cavity by the flow of peritoneal fluid or the malignant ascites at later stages, allowing attachment to secondary sites and initiation of metastasis. Aggregation has been shown to provide the cancer cells signals that improve survival [6,7], resistance to drug therapies [8], and has been associated with an invasive phenotype [9,10]. Advanced stages of disease and metastasis are often associated with an increased volume of ascites within the peritoneal cavity, due to leaky vasculature in the peritoneal wall or tumors releasing higher volumes of fluid, and obstruction of the lymph vessels that reduce drainage of the peritoneal fluid [11]. Ascites is associated with poorer outcomes and lower survival of ovarian cancer patients [11,12]. While very little information is available on nutrient levels in the malignant ascites, glucose levels have been shown to be significantly lower in patients with malignant ascites [16,17]
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