Abstract
Irregular perfusion and related tissue hypoxia is a common feature of solid tumors the role of which in the survival and progression cancer has been gradually recognized. Adaptation and selection mechanisms in hypoxic areas in solid tumors are regulated by Hypoxia Inducible transcriptional factor 1 (HIF1) and other hypoxia mediators and are associated with aggressive clinical behavior in a large spectrum of malignancies. Aggressive forms of lymphatic neoplasias present with solid tumor-like features, also including rapid cell growth, necrosis and angiogenesis, the clinical potential of which is still underestimated. While the role of regional hypoxia in normal B-cell maturation and malignant transformation is becoming evident, the impact of tissue hypoxia on their behavior is not well-understood. Compared to some of the common solid cancer types data for some of the key regulators, such as HIF1 and HIF2, and for their downstream effectors are available in a limited fashion. In the current review we aim to overview the physiological aspects of major hypoxia pathways during B-cell maturation and adaptation-related changes reported in lymphatic neoplasia covering important targets, such as carbonic anhydrases IX and XII (CAIX, CAXII), glucose transporter 1 (GLUT-1) and vascular endothelial growth factor (VEGF). In conclusion, experimental and clinical results direct to important but currently unexploited role of hypoxia-driven resistance mechanisms especially in aggressive forms of B-cell neoplasia.
Highlights
The general presentation and clinical behavior of malignant neoplasias are strongly dependent on tissue oxygenation and nutrient supply
Chemoresistance was associated with the parallel upregulation of the anti-apoptotic Bcl-xL and Hypoxia Inducible transcriptional factor (HIF)-1α and a study reported a positive correlation between these factors and the therapeutic efficacy in non-Hodgkin lymphomas (NHL) cell lines [54]
Glucose transporter type 1 (GLUT1) positivity had a prognostic significance in advanced classical Hodgkin’s lymphoma (cHL), and expression of GLUT1 significantly correlated with Programmed cell Death Ligand 1 (PD-L1) expression
Summary
The general presentation and clinical behavior of malignant neoplasias are strongly dependent on tissue oxygenation and nutrient supply. Lymphomas are consisted of transformed cell masses with at least some circulating capacity, and have long been believed to be independent on tissue blood perfusion. The limited metabolic needs of indolent lymphoproliferations featured by low proliferative activity may be directly served from the circulation. High-grade variants growing in a solid tumor-like fashion require continuously growing perfusion in parallel with the progressive increase of the tumor mass. Large tumor burden and related intra-tumoral pressure dispose to relative tissue perfusion deficit similar to other cancer types. Significant oxygen depletion will result in hypoxic areas turning into focal necrosis frequently seen in aggressive large cell lymphomas [1], and in the progressive variants of Hodgkin’s lymphoma [2]
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