Microenvironmental Hypoxia Induces Dynamic Changes in Lung Cancer Synthesis and Secretion of Extracellular Vesicles

Abstract

Extracellular vesicles (EVs) mediate critical intercellular communication within healthy tissues, but are also exploited by tumour cells to promote angiogenesis, metastasis, and host immunosuppression under hypoxic stress. We hypothesize that hypoxic tumours synthesize hypoxia-sensitive proteins for packing into EVs to modulate their microenvironment for cancer progression. In the current report, we employed a heavy isotope pulse/trace quantitative proteomic approach to study hypoxia sensitive proteins in tumour-derived EVs protein. The results revealed that hypoxia stimulated cells to synthesize EVs proteins involved in enhancing tumour cell proliferation (NRSN2, WISP2, SPRX1, LCK), metastasis (GOLM1, STC1, MGAT5B), stemness (STC1, TMEM59), angiogenesis (ANGPTL4), and suppressing host immunity (CD70). In addition, functional clustering analyses revealed that tumour hypoxia was strongly associated with rapid synthesis and EV loading of lysosome-related hydrolases and membrane-trafficking proteins to enhance EVs secretion. Moreover, lung cancer-derived EVs were also enriched in signalling molecules capable of inducing epithelial-mesenchymal transition in recipient cancer cells to promote their migration and invasion. Together, these data indicate that lung-cancer-derived EVs can act as paracrine/autocrine mediators of tumorigenesis and metastasis in hypoxic microenvironments. Tumour EVs may, therefore, offer novel opportunities for useful biomarkers discovery and therapeutic targeting of different cancer types and at different stages according to microenvironmental conditions.

The CD70-CD27 axis in oncology: the new kids on the block

“…Hypoxia is an important factor of EMT, stem-cell maintenance, invasion, metastasis, angiogenesis and resistance to therapy in solid tumors [98]. In renal cell carcinoma, CD70 induction was reported under hypoxic conditions [99,100].…”

Boosting extracellular vesicle secretion

“…Hypoxia can also be utilized for therapeutic exosome production ( Bister et al, 2020 ). Exposure of cancer cells to severe hypoxic conditions for 24 h resulted in 2- to 3-fold increase in exosome release ( King Hamish et al, 2012 ; Tse et al, 2020 ). Prolonged moderate hypoxia (1% oxygen for 48 h) was less effective for lung cancer cells, and caused only 1.3-fold exosomal elevation (Hamish W King et al, 2012 ).…”

Hemoglobin/Red Blood Cell Distribution Width Ratio in Peripheral Blood Is Positively Associated with Prognosis of Patients with Primary Hepatocellular Carcinoma

“…Second, anemia leads to a decrease in blood oxygen saturation, resulting in “hypoxia in the body”. Under hypoxic conditions, the expression of angiogenesis factors, such as HIF1 and ANGPTL4, is elevated to promote neovascularization, and the rich vascular network provides a metastatic pathway for tumor cells [ 29 , 30 ]. Due to the many factors affecting Hb levels, such as chronic inflammation, aging, and menstruation, the sensitivity and specificity of prognosis in patients with Hb-responsive tumors are not high.…”