Health & Medical Cancer & Oncology

Hypoxic Tumor Microenvironment: Driving NSCLC Tumorigenesis

Hypoxic Tumor Microenvironment: Driving NSCLC Tumorigenesis

Hypoxic Regulation of the LOX Signaling Network Enhances Invasion of NSCLC Cells


The NSCLC tumor microenvironment is rich in ECM components such as collagens, elastins and laminins. Hypoxia is able to increase the stiffness of the ECM through HIF1/LOX-dependent collagen and elastin deposition and cross-linking by fibroblasts. LOX and LOXL2 show increased expression in tissue samples from patients with lung ADC. LOX and LOXL2 are enzymes that catalyze the cross-linking of collagen and elastin by oxidizing lysine residues in these ECM components. Both LOX and LOXL2 contain HREs which HIF1 can bind to and promote their transcription under hypoxia.

LOX and LOXL2 can regulate a number of tumor processes including: increasing cell motility and invasion, enhancing metastasis in vivo as well as increasing proliferation and EMT. LOX can directly downregulate E-cadherin but also activates the EMT transcription factor SNAIL. The ability of LOX and LOXL2 to cross-link collagen appears to be important for activation of integrins and invasion of NSCLC cells. A number of cytokines have been demonstrated to increase LOX expression such as: TGF-β, TNF-α and potentially IL-6. There is also a feedback loop of LOX-induced HIF1α upregulation which may be important for tumor growth. Indeed, co-expression of HIF1α and LOX is associated with decreased survival of NSCLC patients. Of note, one study assessing LOX expression in lung ADC showed that LOX expression was increased not in tumors with loss of p53, but in those lacking another tumor suppressor, LKB1.

LKB1 is a protein kinase that undergoes somatic gene mutations which cause its inactivation. Acting as a tumor suppressor, LKB1 loss when combined with Kras activation in mice resulted in increased numbers of tumors, increased metastasis and reduced survival when compared with Kras activation coupled with loss of classic NSCLC tumor suppressors, p53 and p16Ink4a. Loss of LKB1 expression also causes the stabilization of HIF1 under normoxia, this leads to a metabolic shift to a Warburg-like effect. Adenocarcinoma cells deficient in LKB1 can transdifferentiate into lung SCC when LOX expression is reduced. LOX is partially responsible for LKB1 effects on migration and invasion, but is not involved in LKB1 regulation of cell proliferation.

LKB1 is also inactivated by acetylation; its acetylation is enhanced when the protein deacetylase SIRT1 is downregulated, as occurs under hypoxic conditions. This decreased LKB1 activity causes reduced AMPK activation (LKB1-independent hypoxic deregulation of AMPK also occurs) and contributes to resistance of NSCLC cell lines to cisplatin.

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