NSCLC-HYPOXIA

Executive Summary

• Lung cancer is the most common cancer worldwide with a poor 5-year survival rate.

Molecular biology & pathology of non-small-cell lung cancer

• Research has focused on chromosomal changes, loss of tumor suppressors and amplification of driver oncogenes.
• Recently miRNA, histone and epigenetic biology is coming to the fore.

The NSCLC tumor microenvironment

• Transformed, recruited and differentially activated cells surrounding the tumor form the tumor microenvironment.
• These cells inhibit antitumor immunity while increasing tumor growth.

The hypoxic response pathway

• Cells respond to low oxygen levels through stabilization of the HIF1/2α transcription factors.
• This is a complex system with multiple levels of regulation; however this can be altered in tumor cells through the loss or gain of these pathway proteins.

A dichotomy between HIF1 & HIF2 integrates complex transcriptional networks of hypoxia-regulated genes

• HIF1 and HIF2 regulate the transcription of distinct and overlapping genes responsible for the hypoxic response.
• HIF1 is responsible for metabolic switch and the Warburg effect.
• HIF2 is responsible for NSCLC transformation.
• This effect occurs in the lung epithelium and the surrounding microenvironment.

EMT transcription factors are enhanced by hypoxia

• EMT promoting transcription factors SNAIL, SLUG, TWIST and ZEref-1 are upregulated by hypoxia in NSCLC.

Hypoxic regulation of the LOX signaling network enhances invasion of NSCLC cells

• LOX and LOX2 are upregulated in NSCLC under hypoxia, these proteins control a variety of processes including EMT and invasion.
• Some of these effects are through the tumor suppressor LKref-1.

Hypoxic mechanisms of drug resistance in NSCLC

• Hypoxia contributes to chemotherapy resistance in NSCLC through mechanisms involving drug transporters and CSCs.

Hypoxic induction of NOTCH signaling enhances survival of NSCLC through effects on lung cancer stem cells

• Upregulation of Notch signaling under hypoxic conditions is important for cellular transformation and the prevalence of cancer stem cells in NSCLC.

The immune response to NSCLC and drug resistance in low oxygen

• Hypoxia causes suppression of anticancer immunity on NSCLC through direct effects on lymphocytes and indirectly by tuning tumor-associated macrophages function.