Tumour response to hypoxia: understanding the hypoxic tumour microenvironment to improve treatment outcome in solid tumours

Hypoxia is a common feature of solid tumours affecting their biology and response
to therapy. One of the main transcription factors activated by hypoxia is hypoxia-
inducible factor (HIF), which regulates the expression of genes involved in various
aspects of tumourigenesis including proliferative capacity, angiogenesis, immune
evasion, metabolic reprogramming, extracellular matrix (ECM) remodelling, and
cell migration. This can negatively impact patient outcomes by inducing
therapeutic resistance. The importance of hypoxia is clearly demonstrated by
continued research into finding clinically relevant hypoxia biomarkers, and
hypoxia-targeting therapies. One of the problems is the lack of clinically
applicable methods of hypoxia detection, and lack of standardisation.
Additionally, a lot of the methods of detecting hypoxia do not take into
consideration the complexity of the hypoxic tumour microenvironment (TME).
Therefore, this needs further elucidation as approximately 50% of solid tumours are
hypoxic. The ECM is important component of the hypoxic TME, and is developed
by both cancer associated fibroblasts (CAFs) and tumour cells. However, it is
important to distinguish the different roles to develop both biomarkers and novel
compounds. Fibronectin (FN), collagen (COL) and hyaluronic acid (HA) are
important components of the ECM that create ECM fibres. These fibres are
crosslinked by specific enzymes including lysyl oxidase (LOX) which regulates
the stiffness of tumours and induces fibrosis. This is partially regulated by HIFs.
The review highlights the importance of understanding the role of matrix
stiffness in different solid tumours as current data shows contradictory results
on the impact on therapeutic resistance. The review also indicates that further
research is needed into identifying different CAF subtypes and their exact roles;
with some showing pro-tumorigenic capacity and others having anti-
tumorigenic roles. This has made it difficult to fully elucidate the role of
CAFs within the TME. However, it is clear that this is an important area of
research that requires unravelling as current strategies to target CAFs have
resulted in worsened prognosis. The role of immune cells within the tumour
microenvironment is also discussed as hypoxia has been associated with
modulating immune cells to create an anti-tumorigenic environment. Which
has led to the development of immunotherapies including PD-L1. These
hypoxia-induced changes can confer resistance to conventional therapies,
such as chemotherapy, radiotherapy, and immunotherapy. This review
summarizes the current knowledge on the impact of hypoxia on the TME
and its implications for therapy resistance. It also discusses the potential of
hypoxia biomarkers as prognostic and predictive indictors of treatment
response, as well as the challenges and opportunities of targeting hypoxia in
clinical trials.