Intercellular Communication in Tumor Biology: A Role for Mitochondrial Transfer

Abstract

Intercellular communication between cancer cells and other cells in the tumor microenvironment plays a defining role in tumor development. Tumors contain infiltrates of stromal cells and immune cells that can either promote or inhibit tumor growth, depending on the cytokine/chemokine milieu of the tumor microenvironment and their effect on cell activation status. Recent research has shown that stromal cells can also affect tumor growth through the donation of mitochondria to respiration-deficient tumor cells, restoring normal respiration. Nuclear and mitochondrial DNA mutations affecting mitochondrial respiration lead to some level of respiratory incompetence, forcing cells to generate more energy by glycolysis. Highly glycolytic cancer cells tend to be very aggressive and invasive with poor patient prognosis. However, purely glycolytic cancer cells devoid of mitochondrial DNA cannot form tumors unless they acquire mitochondrial DNA from adjacent cells. This perspective article will address this apparent conundrum of highly glycolytic cells and cover aspects of intercellular communication between tumor cells and cells of the microenvironment with particular emphasis on intercellular mitochondrial transfer.

Mitochondrial Retrograde Signalling and Metabolic Alterations in the Tumour Microenvironment

“…Horizontal transfer of healthy mitochondria from stromal cells in the TME can restore mitochondrial functions and is suggested to participate in the retrograde signalling. Emerging evidences show that ROS stimulates horizontal transfer of mitochondria [39,40].…”

Mitochondrial DNA Affects the Expression of Nuclear Genes Involved in Immune and Stress Responses in a Breast Cancer Model

“…In order to form tumors, these cells acquire mitochondria from donor cells in the host to restore respiration and DHODH activity, allowing them to synthesize nucleic acids and divide. Although cells capable of donating intact mitochondria have been identified in vitro (Berridge et al, 2015;Herst et al, 2018a;Berridge et al, 2020), the physiologically relevant donor cells in different tissues are not known, and the signaling mechanisms that mediate intercellular mitochondrial transfer remain unclear. To better understand the cellular and molecular processes involved in mitochondrial transfer between cells, we investigated transcriptional differences between 4T1 and 4T1ρ 0 cells and cells derived from subcutaneous tumors that grew from 4T1ρ 0 cells (4T1ρ 0 SC) using unbiased MinION long-read cDNA sequencing.…”

Pathogenic Mitochondria DNA Mutations: Current Detection Tools and Interventions

“…The transfer of exogenous mitochondria to an existing endogenous mitochondrial network can lead to an alteration in the function and bioenergetic profile of the recipient cells. Successful intercellular mitochondrial transfer relies on the communication between cells, which includes membrane nanotubes and other cytoplasmic bridges, exosomes, and mitochondrial fusion-fission mechanisms [59].…”