Molecular and functional imaging insights into the role of hypoxia in cancer aggression

Abstract

Hypoxia in cancers has evoked significant interest since 1955 when Thomlinson and Gray postulated the presence of hypoxia in human lung cancers, based on the observation of necrosis occurring at the diffusion limit of oxygen from the nearest blood vessel, and identified the implication of these observations for radiation therapy. Coupled with discoveries in 1953 by Gray and others that anoxic cells were resistant to radiation damage, these observations have led to an entire field of research focused on exploiting oxygenation and hypoxia to improve the outcome of radiation therapy. Almost 65 years later, tumor heterogeneity of nearly every parameter measured including tumor oxygenation, and the dynamic landscape of cancers and their microenvironments are clearly evident, providing a strong rationale for cancer personalized medicine. Since hypoxia is a major cause of extracellular acidosis in tumors, here we have focused on the applications of imaging to understand the effects of hypoxia in tumors and to target hypoxia in theranostic strategies.

Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New H+-Centered Anticancer Paradigm of the Late Post-Warburg Era

“…NHE1 levels are higher in BC tissue than in normal breast tissue, and also in resistant BC cells than in sensitive cells, in a similar fashion to other PTs [ 4 , 10 , 51 , 55 , 56 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ]. Apart from NHE1 overexpression, carbonic anhydrases also have an important role in the pathogenesis of BC, like V-ATPase proton pumps, the Na + –HCO 3 − cotransporter (SLC4A7,NBCn1, MCTs, hypoxia and hypoxia-inducing factor 1 (HIF-1) [ 75 ]. A similar protumoral effect has certain oncogenes, gene mutations and products like BRCA1 and BRCA2 , apart from a dysfunctional p53 [ 76 ] and certain chemicals known to play a role in carcinogenesis [ 77 , 78 ].…”

<p>Hypoxic Non-Small-Cell Lung Cancer Cell-Secreted Exosomal microRNA-582-3p Drives Cancer Cell Malignant Phenotypes by Targeting Secreted Frizzled-Related Protein 1</p>

“…4 Hypoxia was proved to has a powerful impact on tumor progression, including tumor differentiation, growth, and angiogenesis. 5 It was discovered that multiple mechanisms, such as high metabolism and oxygen consumption, lead to tumor cell hypoxia, which in turn activates the hypoxia-inducible factor signaling pathway and thereby promotes the proliferation and migration of tumor cells. 6 Exosomes (exos), small extracellular vesicles with a diameter of 30-200 nm, are shed from the cell membrane into the extracellular matrix.…”

ZnR/GPR39 upregulation of K+/Cl−-cotransporter 3 in tamoxifen resistant breast cancer cells

“…Activation of ZnR/GPR39 requires transient changes in extracellular Zn 2+ , and release of this ion from injured cells was sufficient to activate ZnR/GPR39 signaling [13]. Malignant tumors in-vivo are characterized by regions of cell death due to lack of oxygen, glucose and/or other nutrients [42,43]. Such massive cell death can trigger extracellular Zn 2+ transients and activate ZnR/GPR39 in neighboring breast cancer cells.…”