Tumor stroma: a complexity dictated by the hypoxic tumor microenvironment

Abstract

A lot of effort has been done to study how cancer cells react to low-oxygen tension, a condition known as hypoxia. Indeed, abnormal and dysfunctional blood vessels in the tumor are incapable to restore oxygenation, therefore perpetuating hypoxia, which, in turn, will fuel tumor progression, metastasis and resistance to antitumor therapies. Nevertheless, how stromal components including blood and lymphatic endothelial cells, pericytes and fibroblasts, as well as hematopoietic cells, respond to low-oxygen tension in comparison with their normoxic counterparts has been a matter of investigation in the last few years only and, to date, this field of research remains poorly understood. In general, opposing phenotypes can arise from the same stromal component when embedded in different tumor microenvironments, and, vice versa, different stromal components can have opposite reaction to the same tumor microenvironment. In this article, we will discuss the emerging link between tumor stroma and hypoxia, and how this complexity is translated at the molecular level.

Short Term Hypoxia Synergizes with Interleukin 15 Priming in Driving Glycolytic Gene Transcription and Supports Human Natural Killer Cell Activities

“…Our observation of target cell shifting to late apoptosis through hypoxic NK cell preculture leads us to speculate that oxygen availability during NK cell conditioning can modulate target cell death immunogenicity. This would not withstand hypoxia-mediated immunosuppression through tumor and stroma-derived factors (9,10). In fact, respiratory hyperoxia leads to NK cell-dependent regression of MCA205 pulmonary tumors in mice (72).…”

“…Therefore, they experience oxygen levels ranging from 5% in venous to 13% in arterial blood and down to 3-2% in healthy tissue and below (hypoxia) in the bone marrow, the lymphatic system, at sites of inflammation, and in the tumor microenvironment (3)(4)(5)(6)(7)(8)(9). Tumor hypoxia is thought to support tumor escape from NK cell-mediated cytotoxicity (9,10). In vitro, promotion of NK cell-mediated cell killing by interleukin-2 (IL-2) was reported to be reduced after 96 h at 1% O 2 compared with 20% O 2 , although antibody-dependent cellular cytotoxicity was not affected (11).…”

Malignant transformation of host stromal fibroblasts derived from the bone marrow traced in a dual-color fluorescence xenograft tumor model

“…Neoplastic cells recruit and incorporate adjacent or distant healthy host cells, such as bone marrow-derived cells (BMDCs) for support and essential nutrients (2). Neoplastic cells also recruit fibroblasts, mesenchymal cells, macrophages, endothelial cells, pericytes, hematopoietic cells and extracellular matrix (3), all of which together with other components constitute the tumor microenvironment (TME) (1). Tumor host cells exchange cytokines (such as IL-6, GM-CSF and IL-4), extracellular matrix proteins, enzymes and vesicles in distinct sizes, which promote tumor development, progression and metastases (4,5).…”

Targeting Inflammation to Improve Tumor Drug Delivery

“…This in turn leads to hypoxia and lowering of the microenvironment pH, which further promotes tumor progression. At the same time hypo-perfusion and hypoxia compromise normal immune response, thus rendering the tumor impervious to the immune system [11,12] with an invasive and metastatic phenotype [13]. As expected, reduced blood supply also interferes with effective drug delivery to the tumor [9].…”