Hypoxic Signalling in Tumour Stroma

Abstract

Hypoxia is a common feature in solid tumors and is associated with cancer progression. The main regulators of the hypoxic response are hypoxia-inducible transcription factors (HIFs) that guide the cellular adaptation to hypoxia by gene activation. The actual oxygen sensing is performed by HIF prolyl hydroxylases (PHDs) that under normoxic conditions mark the HIF-α subunit for degradation. Cancer progression is not regulated only by the cancer cells themselves but also by the whole tumor microenvironment, which consists of cellular and extracellular components. Hypoxic conditions also affect the stromal compartment, where stromal cells are in close contact with the cancer cells. The important function of HIF in cancer cells has been shown by many animal models and described in hundreds of reviews, but less in known about PHDs and even less PHDs in stromal cells. Here, we review hypoxic signaling in tumors, mainly in the tumor stroma, with a focus on HIFs and PHDs.

Fibronectin in Cancer: Friend or Foe

“…These findings substantially support that a less rigid FN-enriched matrix within TMEs under normoxia promotes the proliferation of primary tumor cells but limits their capacity of metastasis until the matrix within hypoxic environments depletes FN and becomes stiffened. Abundant evidence indicates that CAFs and macrophages are able to change their phenotypes upon hypoxic stimulation to foster a stiffer matrix which in turn aggravating neovascular abnormality and facilitating the subsequent distant organ metastasis [237,252,253]. Indeed, hypoxia-induced CAF and macrophage phenotype alterations actively participate in promoting tumor intravasation, an essential event predisposing tumor cells en route from the circulation to distant organs [136,198,254,255].…”

Tumor Microenvironment: Extracellular Matrix Alterations Influence Tumor Progression

“…Under hypoxic conditions, prolyl-hydroxylases are inhibited, leading to the stabilization of HIFs that induces the expression of various genes implicated in tumor progression. Moreover, hypoxic responses include the unfolded protein response (UPR) and mammalian target of rapamycin (mTOR) signaling (9). mTOR signaling, through the phosphoinositide 3-kinase (PI3K)/Akt pathway, largely contributes to the regulation of cell survival, growth, and metabolism through phosphorylation of the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1 protein) and ribosomal protein S6 kinase (10).…”

Young and elderly oral squamous cell carcinoma patients present similar angiogenic profile and predominance of M2 macrophages: Comparative immunohistochemical study

“…Hypoxia is a frequent feature in solid neoplasms, closely related to cancer progression . The hypoxia‐inducible transcription factors (HIFs) are the main regulators of the adaptive hypoxic responses in cancer, including cell proliferation, differentiation, angiogenesis, metastasis, tumor immune response, and resistance to therapy .…”

“…Hypoxia is a frequent feature in solid neoplasms, closely related to cancer progression . The hypoxia‐inducible transcription factors (HIFs) are the main regulators of the adaptive hypoxic responses in cancer, including cell proliferation, differentiation, angiogenesis, metastasis, tumor immune response, and resistance to therapy . In fact, the HIF‐1α seems to be an independent prognostic marker in OSCC, being relevant that the carcinoma cells, under hypoxic conditions, can promote macrophage recruitment and proangiogenic M2‐polarized phenotype, thereby promoting tumor growth …”

“…[42][43][44] The hypoxia-inducible transcription factors (HIFs) are the main regulators of the adaptive hypoxic responses in cancer, including cell proliferation, differentiation, angiogenesis, metastasis, tumor immune response, and resistance to therapy. 42,45,46 In fact, the HIF-1α seems to be an independent prognostic marker in OSCC, 47 being relevant that the carcinoma cells, under hypoxic conditions, can promote macrophage recruitment and proangiogenic M2-polarized phenotype, thereby promoting tumor growth. [43][44][45][46] Considering that the aging process acts, among others, on the immune system and tissue remodeling, there is a great need to elucidate the effects of immunosenescence on the TAM population and angiogenesis in OSCC.…”