Tumor Hypoxia As an Enhancer of Inflammation-Mediated Metastasis: Emerging Therapeutic Strategies

Abstract

Metastasis is the leading cause of cancer-related deaths. Recent research has implicated tumor inflammation as a promoter of metastasis. Myeloid, lymphoid, and mesenchymal cells in the tumor microenvironment promote inflammatory signaling amongst each other and together with cancer cells to modulate sustained inflammation, which may enhance cancer invasiveness. Tumor hypoxia, a state of reduced available oxygen present in the majority of solid tumors, acts as a prognostic factor for a worse outcome and is known to have a role in tumor inflammation through the regulation of inflammatory mediator signals in both cancer and neighboring cells in the microenvironment. Multiple methods to target tumor hypoxia have been developed and tested in clinical trials, and still more are emerging as the impacts of hypoxia become better understood. These strategies include mechanistic inhibition of the hypoxia inducible factor signaling pathway and hypoxia activated pro-drugs, leading to both anti-tumor and anti-inflammatory effects. This prompts a need for further research on the prevention of hypoxia-mediated inflammation in cancer. Hypoxia-targeting strategies seem to have the most potential for therapeutic benefit when combined with traditional chemotherapy agents. This paper will serve to summarize the role of the inflammatory response in metastasis, to discuss how hypoxia can enable or enhance inflammatory signaling, and to review established and emerging strategies to target the hypoxia-inflammation-metastasis axis.

The IL1β-IL1R signaling is involved in the stimulatory effects triggered by hypoxia in breast cancer cells and cancer-associated fibroblasts (CAFs)

“…Subsequently, HIF-1α binds to the hypoxia response elements regulating the transcription of genes implicated in critical aspects of cancer biology as angiogenesis, stem cell maintenance, metabolic reprogramming, epithelial-mesenchymal transition, invasion, metastasis and resistance to therapy [9,56,57]. Likewise, hypoxia-activated HIF-1α plays a role in the tumor-related inflammation leading to worse clinical outcomes in diverse types of cancers including breast tumors [58]. These events may occur through the HIF-1α dependent regulation of signaling mediators and inflammatory genes in both cancer and neighboring cells within the tumor microenvironment [58].…”

“…Likewise, hypoxia-activated HIF-1α plays a role in the tumor-related inflammation leading to worse clinical outcomes in diverse types of cancers including breast tumors [ 58 ]. These events may occur through the HIF-1α dependent regulation of signaling mediators and inflammatory genes in both cancer and neighboring cells within the tumor microenvironment [ 58 ]. Moreover, the pro-tumorigenic action of HIF-1α may occur through its interaction with various signaling pathways like transforming growth factor-β, Wnt/β-catenin, Notch and GPCRs [ 12 , 59 – 61 ].…”

Annexin A1 regulates EGFR activity and alters EGFR-containing tumour-derived exosomes in head and neck cancers

“…ANXA1 is mainly an anti-inflammatory protein with important roles in the innate and adaptive immune response [7]. Inflammation has been shown to alter the tumour microenvironment as well as tumour immune responses and to induce tumour hypoxia [51,52]. Additionally, hypoxia induces a chronic inflammatory state which further reduces immune responses within the tumour microenvironment [53,54].…”

Epithelial ovarian cancer

“…Research aimed at delineating novel resistance mechanisms is needed. Another area of investigation is the immune infiltration and tumour hypoxia 105 , and how modulating the microenvironment may prompt responses to therapy. Since preliminary results of immunotherapy as single agent showed low response rates in HGSOC 106 , novel approaches are based on combination strategy and T-cell therapy 107 .…”