Regulation of Tumor Progression by Programmed Necrosis

Abstract

Rapidly growing malignant tumors frequently encounter hypoxia and nutrient (e.g., glucose) deprivation, which occurs because of insufficient blood supply. This results in necrotic cell death in the core region of solid tumors. Necrotic cells release their cellular cytoplasmic contents into the extracellular space, such as high mobility group box 1 (HMGB1), which is a nonhistone nuclear protein, but acts as a proinflammatory and tumor-promoting cytokine when released by necrotic cells. These released molecules recruit immune and inflammatory cells, which exert tumor-promoting activity by inducing angiogenesis, proliferation, and invasion. Development of a necrotic core in cancer patients is also associated with poor prognosis. Conventionally, necrosis has been thought of as an unregulated process, unlike programmed cell death processes like apoptosis and autophagy. Recently, necrosis has been recognized as a programmed cell death, encompassing processes such as oncosis, necroptosis, and others. Metabolic stress-induced necrosis and its regulatory mechanisms have been poorly investigated until recently. Snail and Dlx-2, EMT-inducing transcription factors, are responsible for metabolic stress-induced necrosis in tumors. Snail and Dlx-2 contribute to tumor progression by promoting necrosis and inducing EMT and oncogenic metabolism. Oncogenic metabolism has been shown to play a role(s) in initiating necrosis. Here, we discuss the molecular mechanisms underlying metabolic stress-induced programmed necrosis that promote tumor progression and aggressiveness.

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

“…A Top1 DNA-damaging CuC inhibitor induces necrotic cell death. To facilitate cell destruction, necrosis is activated by ROS or ATP metabolic stresses in crosstalk with apoptosis [ 160 ]. When the intracellular energy/ATP level is low, the apoptotic cell death is converted into necrosis [ 161 ] ( Figure 5 A).…”

Obesity Promotes Cooperation of Cancer Stem-Like Cells and Macrophages to Enhance Mammary Tumor Angiogenesis

“…Although larger, Met-1 tumors from obese mice demonstrated significantly decreased necrosis compared to tumors from lean mice (p = 0.007, Figure 3A). An underlying cause of necrosis may be an insufficient blood supply [31]. To detect endothelial cells, tumors sections from Met-1 and EO771 tumors from obese and lean mice were stained with anti-CD31 antibodies.…”

Honokiol: A Review of Its Anticancer Potential and Mechanisms

“…Necrosis is known as unprogrammed cell death whereby cell swelling and destabilisation of the cell membrane results in the leakage of cellular cytoplasmic contents into the extracellular space, thus causing inflammation [116]. Besides apoptosis, honokiol has also been found to induce necrotic cell death in MCF-7 (40 µg/mL honokiol) [117], human oesophageal adenocarcinoma cells CP-A and CP-C [118], and primary human acute myelogenous leukemia HL60 [85] via p16ink4a pathway by targeting cyclophilin D to affect several downstream mechanisms.…”