Chloroquine mediates tumor vessel normalization in an autophagy-independent manner.
Major finding: Chloroquine mediates tumor vessel normalization in an autophagy-independent manner.
Mechanism: Chloroquine alters endosomal NOTCH1 trafficking and promotes NOTCH1 signaling in endothelial cells.
Impact: Chloroquine reduces tumor invasion and metastasis and enhances chemotherapy delivery and response.
The anticancer properties of the antimalarial agent chloroquine are believed to result from the disruption of cancer cell autophagy, an essential nutrient-generating process in times of cellular stress. Maes, Kuchnio, and colleagues investigated whether the anticancer activity of chloroquine is also mediated by effects on stromal cells and whether these effects are dependent on autophagy. Chloroquine treatment reduced the growth and proliferation of melanoma cell lines in mice with concomitant decreases in the degradation of autophagy-selective substrates. Surprisingly, chloroquine treatment reduced tumor necrosis in vivo, but also resulted in less invasive tumors that exhibited impaired intravasation and diminished metastatic potential. Chloroquine-mediated effects on cancer cell invasion were not observed in vitro, suggesting an indirect effect on cancer cells through regulation of the tumor stroma. In support of this idea, chloroquine treatment induced normalization of tumor vasculature, including decreased hypoxia and improved tumor vessel structure and function, potentially contributing to a less stressed tumor microenvironment. In addition, increased vascular normalization in response to chloroquine enhanced the delivery and efficacy of chemotherapy. Tumor vessel normalization occurred independently of autophagy in cancer cells and endothelial cells, and was instead mediated via modulation of endosomal degradation by chloroquine. Assessment of a panel of angiogenic molecules in endosomal compartments revealed altered trafficking of NOTCH1 to late endosomes after chloroquine treatment. Chloroquine induced the accumulation of NOTCH1 in late endosomes of endothelial cells, which resulted in increased enzymatic cleavage and formation of the transcriptionally active NOTCH1 intracellular domain. Inhibition of NOTCH1 signaling in endothelial cells eliminated chloroquine-induced tumor vessel normalization and its effects on metastasis and tumor necrosis. Taken together, these observations suggest that the anticancer activity of chloroquine is also mediated by autophagy-independent normalization of tumor vessels via sustained activation of NOTCH1 signaling in late endosomes.
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