Targeting tumor hypoxia and its effects

Tumor hypoxia (oxygen deprivation) develops due to uncontrollable cell proliferation, altered metabolism, and abnormal tumor blood vessels. As a tumor grows, it quickly outstrips its blood supply, necessitating the formation of new blood vessels to continue to deliver oxygen and nutrients to the tumor. To orchestrate this, cancer cells boost the production of growth factors such as VEGF (vascular endothelial growth factor) to stimulate the formation of blood vessels in a process known as angiogenesis. Unlike the well-formed, organized, and highly efficient blood vessels in healthy tissue, tumor blood vessels are malformed, disorganized, and inadequate to meet the metabolic demands of a growing tumor. As a result, blood flow in tumors is non-uniform and chaotic. Some regions of the tumor will be normoxic (sufficiently oxygenated), whereas most regions will be hypoxic (oxygen-deprived). The most aggressive and treatment-resistant cancer cells are usually located in the chronically hypoxic regions of the tumor.

One of the main reasons that people die prematurely of cancer is treatment failure due to physiological barriers to successful cancer treatment. It turns out, chronic tumor hypoxia plays a central role in limiting the effectiveness of anti-cancer therapy. The “master switches” orchestrating cancer’s response to low oxygen levels are called nuclear erythroid-related factor 2 (Nrf2) and hypoxia-inducible factor 1-alpha (HIF-1α). Tumor hypoxia stimulates the formation of and stabilizes (activates) Nrf2 and HIF-1α which gives cancer cells a competitive advantage over normal cells.

Accumulation of stabilized Nrf2 and HIF-1α promotes numerous adaptive changes within tumor cells, including overexpression of monocarboxylate transporters 1 and 4 (MCT1 and MCT4) and carbonic anhydrase 9 (CAIX), that trigger the proliferation and survival of cancer cells and cancer stem cells through metabolic reprogramming, increased iron utilization, extracellular acidification from lactate and carbonic acid, angiogenesis, tumor invasion and migration, metastasis, stimulation of cancer’s antioxidant defense mechanisms, genetic instability, resistance to apoptosis and ferroptosis, immunosuppression, increased tumor interstitial fluid pressure and reduced drug delivery, upregulation of cytoprotective genes that rapidly metabolize and eliminate chemotherapeutics and reduce treatment efficacy, and disease recurrence. Even in the absence of tumor hypoxia, the mere presence of inflammatory cytokines IL-1, IL-6, TNF-α, and TGF-β in the tumor microenvironment can mimic the presence of hypoxia by stimulating the production of CAIX.

To combat all of this and improve treatment outcomes, we have the following tools at our disposal to modify the tumor microenvironment by decreasing tumor hypoxia, inhibiting Nrf2, HIF-1α, VEGF, MCT1, MCT4, and CAIX, reducing extracellular acidification, lowering interstitial fluid pressure, and decreasing inflammatory cytokines: