Perspectives on Hypoxia Signaling in Tumor Stroma

Abstract

Hypoxia is a well-known characteristic of solid tumors that contributes to tumor progression and metastasis. Oxygen deprivation due to high demand of proliferating cancer cells and standard of care therapies induce hypoxia. Hypoxia signaling, mainly mediated by the hypoxia-inducible transcription factor (HIF) family, results in tumor cell migration, proliferation, metabolic changes, and resistance to therapy. Additionally, the hypoxic tumor microenvironment impacts multiple cellular and non-cellular compartments in the tumor stroma, including disordered tumor vasculature, homeostasis of ECM. Hypoxia also has a multifaceted and often contradictory influence on immune cell function, which contributes to an immunosuppressive environment. Here, we review the important function of HIF in tumor stromal components and summarize current clinical trials targeting hypoxia. We provide an overview of hypoxia signaling in tumor stroma that might help address some of the challenges associated with hypoxia-targeted therapies.

Payload Delivery: Engineering Immune Cells to Disrupt the Tumour Microenvironment

“…Solid tumours are not only challenging for CAR T cells to infiltrate, they are also a highly immunosuppressive arena in which cell-mediated cytotoxicity must take place. Metabolic obstacles including hypoxia, low pH, and depletion of essential nutrients such as amino acids and glucose, are common features of the solid tumour microenvironment (TME) that can markedly suppress immune cell function [ 36 , 37 , 38 ]. Further obstacles are posed by immunosuppressive cell types such as tumour-associated macrophages (TAMs), T regulatory cells (Tregs), and myeloid-derived suppressor cells (MDCSs) [ 39 , 40 ]; these cells express high levels of immune inhibitory molecules, such as programmed death receptor ligands (PD-L1 and PD-L2), galectin-9, and the so-called herpes virus entry mediator (HVEM), and secrete large amounts of anti-inflammatory cytokines, including transforming growth factor-β (TGF-β and interleukin (IL)-10 [ 39 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ].…”

“…Hypoxia is a hallmark of solid tumours that contributes significantly to immunosuppression within the TME [ 49 ]. Disorganised cell growth, metabolism, and vascularisation contribute to reduced oxygen availability within tumours, ultimately leading to increased levels of reactive oxygen species—namely hydrogen peroxide (H 2 O 2 )—and a state of oxidative stress within the TME that thwarts anti-tumour immunity [ 36 ]. To counteract this, Ligtenberg et al engineered CAR T cells with genes that encode catalases, enzymes which metabolise H 2 O 2 into water and oxygen, and thus ameliorate oxidative stress.…”

Engineering defected 2D Pd/H-TiO2 nanosonosensitizers for hypoxia alleviation and enhanced sono-chemodynamic cancer nanotherapy

“…It should be recognized that hypoxia, the prevalent hallmark of the overwhelming majority of solid tumors induced by rapid proliferation and aberrant neovasculature, is a bottleneck for cancer treatment [ 26 – 28 ]. Definitely, the low oxygen tension not only contributes to tumor aggressiveness and metastasis but also results in compromised cytotoxic effect [ 29 , 30 ].…”

Accurate Three-Dimensional Thermal Dosimetry and Assessment of Physiologic Response Are Essential for Optimizing Thermoradiotherapy

“…Hypoxia is also known to negatively influence treatment response to chemotherapy [ 27 ] and immunotherapy [ 20 , 28 ], as well as contributing to tumor aggressiveness [ 29 , 30 , 31 , 32 , 33 ]. A recent Special Issue in Cancers contained several original reports and contemporary review papers on the subject of tumor hypoxia [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. In this review, we will consider how thermal dose affects tumor hypoxia and, in turn, whether changes in hypoxia in response to thermoradiotherapy can influence treatment outcome.…”