1. Gallagher, Amy

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New research on ovarian cancer has led to a greater understanding of how ovarian cancer cells adapt to survive and proliferate in the peritoneal cavity, while bringing scientists closer to targeted treatments that suppress the growth of ovarian cancer.

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Researchers at Virginia Tech University showed that structures inside the cells change as the disease progresses from benign to malignant, helping the cells to grow in an otherwise hostile environment of low nutrients and oxygen.


Understanding how these cellular adaptations are regulated could herald new targeted treatment options against the fifth-leading cause of cancer-related deaths in women, said lead author Eva Schmelz, PhD, Professor and Scientific Director at Virginia Tech University.


"The first line of treatment today for ovarian cancer is debulking surgery," she said. "That removes cancer cells that are attached to an organ or the lining of the abdomen, but that is not all there is in the case with ovarian cancer. After removing the primary tumor from the ovaries or fallopian tube, thousands of tiny tumor cells are still swimming around even after surgery that can't be taken out. What happens when these cells aggregate, which is a survival signal, we don't know."


Schmelz and her colleagues compared the structures inside cells representing different stages of ovarian cancer, including after aggregation, which enhances the cancer cells' survival, she noted. "We found that one of these structures, the mitochondria, known as the 'battery pack' of the cell, changed shape and function to adapt to the hostile conditions in the peritoneal cavity, allowing aggressive cancerous cells to grow and take hold."


Metabolism & Energy Production

Schmelz and her colleagues recently published a paper which showed that, when cells aggregate, the cells reduce in energy production.


As the ovarian cancer progressed, the mitochondria changed from a filamentous network to a highly fragmented form, said Joe Grieco, graduate student in the Schmelz lab and leading author.


"Our previous work has shown the metabolism of cells changed as ovarian cancer progressed," added Schmelz. "This fragmentation and known changes in the way mitochondria function in this state are how the cells adapt to an environment that is low in nutrients and oxygen. It also allows the cells to escape treatments commonly used in ovarian cancer patients, so they can continue to proliferate."


To preserve energy, this reduces the function of the mitochondria and they grow slowly so they need less energy. "We wanted to build on this by looking inside the cells to identify any structural differences," said Schmelz.


Furthermore, the cells exfoliating from this cancerous mass can then spread onwards throughout the peritoneal cavity via the fluid in the abdomen. "At this stage, a patient's survival rates are just 30 percent, even if the original tumor is removed," explained Schmelz. "Chances are greatly increased to over 90 percent if the cancer diagnosis is identified in the initial stages."


Ovarian Cancer as Precancerous

Unfortunately, however, early stages of ovarian cancer are hard to detect, she said.


"There are very few reliable biomarkers," said Schmelz. "Metastatic cancer cells are transported in the blood or the lymphatic system, but the bloodstream is much faster than the lymphatic stream. The stress kills most of the cells. In the peritoneal cavity, however, that is not the case."


There is not one marker that would encompass all ovarian cancers; a non-invasive method like a blood sample would be best to detect early stages. "Ovarian cancer encompasses a heterogenous group of malignancies that vary in etiology and gene expression," said Schmelz. "There is a different gene expression that can enhance or delay the growth."


She noted that most women do not have any symptoms in the beginning stages, and when symptoms are felt, it is usually too late. As such, ovarian cancer is often fatal. "The most aggressive ovarian cancer originates from cancerous cells in the fallopian tubes," she said.


Cancer Cells in Abdomen Fluid

Ovarian cancer is not in the top 10 of diagnosed cancers, but it is in the top 10 that women die of, Schmelz noted. "If we understand how ovarian cancer cells survive in the fluid of the abdomen as they spread around the peritoneal cavity, we may be able to develop specific therapeutics and interventions to suppress cancerous outgrowths of cells from the original tumor."


Ovarian cancer cells survive in the fluid of the abdomen; however, this is not unique to ovarian cancer, she said. Ascites, which is low in oxygen and nutrients, is the accumulation of fluid in the peritoneal cavity, causing abdominal swelling, and is caused by cancer that most often occurs with advanced or recurrent cancer. Schmelz said a research project has been initiated to look at what is in there.


"By examining cells developed from the ovaries of mice, any changes could be attributed to the progression of the disease rather than any differences between individuals," she said.


The researchers used a wide variety of microscopy techniques to obtain 2D images and 3D models of the mitochondria to identify and measure their structure at different stages of the cancer.


Future Research Studies

"Future studies will identify how the changes we have identified inside the cells are regulated by characterizing specific cell signaling pathways to create targets for therapies that limit the viability and spread of ovarian cancer cells," Schmelz noted. "We will also look at mechanisms to see how the cells are regulated and how a cell can regulate the mitochondria form and function, then actually uses those inhibitors in those pathways to see if it reduces the metastatic capacity.


"Further research will identify specific signaling pathways to understand how the mitochondria biodynamics is regulated in this instance, then we will target that, and create adaptation to that condition so the cells will die," she explained.


Schmelz's team at Virginia Tech hopes these findings will form the basis of research to bring new treatments for this devastating disease.


Amy Gallagher is a contributing writer.