A study performed by The Wistar Institute has revealed that oxygen-deprived breast cancer cells transmit messages that cause oncogenic modifications in the surrounding healthy epithelial cells.
Image Credit: The Wistar Institute.
Packed into particles, known as extracellular vesicles (EVs), these messages reprogram the shape and position of mitochondria inside the recipient normal cells to eventually support the morphogenesis of deregulated tissues. The study results were recently published in the Developmental Cell journal.
It is well known that cancer cells ‘talk’ to their neighboring normal cells all the time and this is important to promote cancer progression. How that happens and what signals are being transferred from one cell to another are still very much open questions. A better understanding of this process may give us important clues about how tumors hijack nearby normal cells to promote disease recurrence.”
Dario C. Altieri, MD, Study Lead Author, President, and CEO, The Wistar Institute
Dr Altieri is also the director of the Cancer Center at Wistar Institute and the Robert & Penny Fox Distinguished Professor.
For their research works, Dr Altieri’s research team grew breast cancer cells in a low-oxygen environment to imitate a condition called hypoxia—a hallmark of the microenvironment that surrounds a majority of the solid tumors—and analyzed the EVs discharged by these cells.
EVs are small structures surrounded by a double-membrane layer and discharged by a majority of the cells to convey different kinds of molecules and data to other cell types. Therefore, vesicles are a significant means of intercellular interaction. In this research, the team focused on tiny EVs (sEV) that have a size of 30 to 150 nm.
The team then incubated normal breast epithelial cells with sEVs discharged by cells maintained in hypoxia. This was done to establish the impacts of sEVs created by cancer cells on normal adjacent cells.
The researchers observed that normal recipient cells developed an increased ability to migrate in culture, which consecutively corresponded with a redistribution of their mitochondria to the periphery of cells. This was found to be consistent with the crucial role played by mitochondria in supporting the motility of cells, which was earlier explained by the Altieri laboratory.
Apart from the modulation of mitochondrial behavior, the researchers observed that sEV discharged by hypoxic breast cancer cells caused major modifications in the expression of genes in the normal recipient cells, with the activation of numerous routes of cytoskeletal organization, cell motility, and cell-to-cell contact. Moreover, cells treated with sEVs showed increased pro-inflammatory responses and reduced cell death.
Altieri and collaborators set out to detect Integrin-Linked Kinase (ILK) as the key signaling component packed in sEVs, which accounts for increased migration of recipient cells as well as mitochondrial variations. Activation of ILK signaling, in turn, profoundly influenced the morphogenesis of normal tissues.
Using 3D cell models of the development of normal mammary glands, the researchers found that when hypoxic cancer cells are exposed to sEVs, it usually disrupted the architecture of normal mammary glands and induced numerous traits of oncogenic transformation, such as reduced cell death, deregulated proliferation of cells, morphological changes, and appearance of markers of epithelial-mesenchymal transition (EMT)—a process that imparts mobility to cancer cells and the ability to move from the primary location.
Our findings indicate that breast cancer cells may use sEVs to enable both local and distant disease progression. Based on these observations, we suggest that therapeutic targeting of ILK or mitochondrial reprogramming may provide novel strategies to disrupt these pro-tumorigenic changes in the microenvironment.”
Irene Bertolini, PhD, Study First Author, The Wistar Institute
Bertolini is also a postdoctoral fellow in the Altieri laboratory.
Bertolini, I., et al. (2020) Small Extracellular Vesicle Regulation of Mitochondrial Dynamics Reprograms a Hypoxic Tumor Microenvironment. Developmental Cell. doi.org/10.1016/j.devcel.2020.07.014.