Hypoxic control of metastasis

Abstract

Metastatic disease is the leading cause of cancer-related deaths and involves critical interactions between tumor cells and the microenvironment. Hypoxia is a potent microenvironmental factor promoting metastatic progression. Clinically, hypoxia and the expression of the hypoxia-inducible transcription factors HIF-1 and HIF-2 are associated with increased distant metastasis and poor survival in a variety of tumor types. Moreover, HIF signaling in malignant cells influences multiple steps within the metastatic cascade. Here we review research focused on elucidating the mechanisms by which the hypoxic tumor microenvironment promotes metastatic progression. These studies have identified potential biomarkers and therapeutic targets regulated by hypoxia that could be incorporated into strategies aimed at preventing and treating metastatic disease.

Hypoxia regulates ANXA1 expression to support prostate cancer cell invasion and aggressiveness

“…Both initiation and progression of tumorigenesis are promoted by HIF signaling and tumors use several strategies to trigger this pathway. 39 Interestingly, the accumulation of HIF-1 has been associated with ANXA1 expression increase. 7 The role of this protein in PCa development and progression is still debated, however we have recently showed that the protein plays a significant part in regulating aggressive behaviors of a chemoresistant sub-line of DU145 PCa cells.…”

“…37 The evolution from hormone-dependent to hormone-independent PCa is supposed to be an effect of genetic alterations, 38 however numerous evidences are accumulating about the role of tumor microenvironment on the outset of a metastatic disease. 39 Hypoxia is an essential feature of the microenvironment of several solid tumors including those of PCa. 40,41 One of the key mechanisms mediating the adaptation to low oxygen conditions is the induction of HIF-1, a factor with critical roles in many aspects of cancer biology.…”

NHR‐49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

“…Impaired stress responses contribute to human age‐related diseases such as diabetes and neurodegenerative disorders (Hetz, Chevet & Harding, 2013; Lin & Beal, 2006), and likely also contribute to aging (Hekimi, Lapointe & Wen, 2011; Shore & Ruvkun, 2013). However, these adaptive responses also protect pathogens and cancer cells against cytotoxic drugs and the immune system (Leprivier, Rotblat, Khan, Jan & Sorensen, 2015; Rankin & Giaccia, 2016). Accordingly, there is widespread interest in defining the mechanisms involved in coordinating these transcriptional responses.…”

ARNT/HIF‐1β links high‐risk 1q21 gain and microenvironmental hypoxia to drug resistance and poor prognosis in multiple myeloma

“…As a landmark of tumor microenvironment, hypoxia is involved in virtually all aspects of cancer pathogenesis 10. Hypoxia triggers various cellular responses primarily via the HIF family 11, 12.…”

“…HIF‐1β predominately binds HIF‐1α or aryl hydrocarbon receptor (AhR) to form heterodimer complexes that regulate transcription of target genes involved in various physiological and pathological processes, including cancer. In the former, the role of the HIF‐1 complex consisting of HIF‐1α or ‐2α, a transactivating subunit that is inducible (eg, in response to hypoxia), and HIF1β, a regulatory subunit that is often considered as constitutively expressed and unaffected by hypoxia, has been well documented in tumor progression,11 tumor‐stroma interaction,12 metastasis,10 etc. In the latter, the AhR/ARNT complex binds to dioxin‐responsive elements (DREs) to induce transcription of target genes that encode drug‐metabolizing enzymes (eg, cytochrome P450 1A1) as well as proteins governing cell proliferation, differentiation, and apoptosis, which most likely facilitates carcinogenesis and tumor promotion 16.…”