M3L8 Vacularisation, hypoxia, acidosis, and the Warburg effect

• Niche construction - spontaneous interaction between activated stromal cells and normal cells that enables initiated/transformed clone survival

• Niche expansion - microenvironment that generates secreted factors that remodel local tissue, concurrent with initiates clone expansion and parallels tumour promotion

• Niche maturation - recruitment of bone marrow derived cells as well as resident cells (esp. fibroblasts) dries niche maturation from a nascent to an established TME

• At some point a successful niche evolves and matures into a dynamic feedback system

• Niche types (not mutually exclusive to each other):

  • Hypoxic 

  • Acidic

  • Immune microenvironmnet

  • Innervated niche

  • Metabolism microenvironment

  • Mechanical microenvironment

• Tumour growth depends on the adaptive responses exhibited by tumour cells in response to the evolving niche

Hypoxia

• Adaptation to hypoxia is through HIFs

• HIF-dependent signalling promotes adaptation and selection of cancer and stromal cells to the surrounding consitions, promoting pro-tumourigenic changes

• HIF family of TFs includes HIF1, HIF2, HIF3 which all contain an oxygen sensitivity HIF-α subunit which dimerises with the constitutively expressed HIF-β subunit

• Under normoxia. HIFs undergo ubiquitination mediated by PHDs (oxygen-dependent hydroxylase family) and pVHL (von Hippel-Lindau tumour suppressor protein)

  • Activity of PHD is prohibited under hypoxia

• In the nucleus HIF-α binds to hypoxia response elements (HRE) to promote gene expression of genes with this promoter

• The HIF1α gene has a DNA binding and dimerisation domain, oxygen-dependent degradation domain, and transactivation domain

  • PHDs and FIH can hydroxylate oxygen-dependent degradation domain and transactivation domain to mark for degradation 

  • FIH hydroxylation of transactivation domain without PHD hydroxylation stabilise HIF1α

  • CAD active/NAD active (high hypoxia) vs CAD inactive/NAD (lower hypoxia) active states of HIF1α reflects differential activation of target genes in response to different levels of hypoxia

• HIF-mediated hypoxic impact - secretion of signalling molecules,  metabolic changes, switch to aerobic glycolysis

• Hypoxia leads to dyregulation of fibroblasts that may support tumourigenesis

  • Fibroblasts can be transformed into CAFs, leading to ECM remodelling that supports metastases

• Different levels of hypoxia can trigger varying responses - eg. cell death in severe cases, immune regulation in lower levels of hypoxia

• Immediate response may be angiogenesis to promote reoxygenated

  • In a 3D TME, tumour cells can be exposed to fluctuating O2 response leading to cycling hypoxia (acute hypoxia/anoxia followed by reoxygenation) and differential oxygen graduents for different time periods

  • Fluctuations can lead to differential biology based on hypoxia severity, duration, or whether it is terminated by cell death/reoxygenation

• Hypoxia/ROS can cause permanent DNA damage

Warburg effect

• Warburg effect - aerobic glycolysis in cancer

• Reverse Warburg effect - two-compartment model where stromal cells are induced by cancer cells to undergo aerobic glycolysis and transfer products back to cancer cells to be used for OXPHOS

Acidosis

• High metabolic demand of cancer cells —> accumulation of H+ in TME due to lactic acid production from the Warburg effect

• Disorganised tumour vasculature prevents efficient wash-out of H+

• Genes involved in mitochondrial energy metabolism facilitate cancer cell survival under acidotic stress

• OXPHOS inhibition kills cancer cells in low pH conditions

  • This is because without oxygen normal cells can do glycolysis

  • However H+ negatively feeds back to inhibit glycolysis, thus cancer cells relying on aerobic glycolysis will die in low pH TME

• Dysregulated pH is an emerging hallmark of cancer (low pH outside cells, higher pH inside - reversed pH gradient)

  • Carbonic anhydrase IV (CAIX) is a pH sensor upregulated for this

  • Proton transporters pump out H+, thus upregulated

• Can cause immune suppression in TME due to low pH or decrease drug uptake

Vascularisation and angiogenesis

• Compared to normal vasculature, tumour vessels exhibit immature hierarchy with discontinuous endothelial lining, incomplete pericyte coverage and leakiness —> elevated interstitial pressure, narrowed lumen, impaired O2/drug delivery to tumour

• Tumour endothelial cells with overexpressed VEGF receptors replace the normal ones and make the vessels more sensitive to VEGF.

• Antitumor immune function is retarded due to diminished T cell extravasation

• Cells lacking O2/nutrients become nectrotic, thus angiogenesis is triggered to develop tumour vasculature