Hypoxia in Tumors: Pathogenesis-Related Classification, Characterization of Hypoxia Subtypes, and Associated Biological and Clinical Implications

Abstract

Hypoxia is a hallmark of tumors leading to (mal-)adaptive processes, development of aggressive phenotypes and treatment resistance. Based on underlying mechanisms and their duration, two main types of hypoxia have been identified, coexisting with complex spatial and temporal heterogeneities. Chronic hypoxia is mainly caused by diffusion limitations due to enlarged diffusion distances and adverse diffusion geometries (e.g., concurrent vs. countercurrent microvessels, Krogh- vs. Hill-type diffusion geometry) and, to a lesser extent, by hypoxemia (e.g., in anemic patients, HbCO formation in heavy smokers), and a compromised perfusion or flow stop (e.g., due to disturbed Starling forces or intratumor solid stress). Acute hypoxia mainly results from transient disruptions in perfusion (e.g., vascular occlusion by cell aggregates), fluctuating red blood cell fluxes or short-term contractions of the interstitial matrix. In each of these hypoxia subtypes oxygen supply is critically reduced, but perfusion-dependent nutrient supply, waste removal, delivery of anticancer or diagnostic agents, and repair competence can be impaired or may not be affected. This detailed differentiation of tumor hypoxia may impact on our understanding of tumor biology and may aid in the development of novel treatment strategies, tumor detection by imaging and tumor targeting, and is thus of great clinical relevance.

Cycling hypoxia: A key feature of the tumor microenvironment

“…Indeed, the disorganization of the blood structure characterized by excessive branching, tortuosity, shunts, blind ends and an inconstant diameter leads to an irregular dispersion of erythrocytes in the blood flow and thus to an inefficient erythrocyte flux. Moreover, the irregular erythrocyte flux can also be caused by obstruction of blood vessels by tumor cells, leukocytes, erythrocytes and platelet aggregates that causes temporary occlusions [26]. In addition, the transient limitation of perfusion has also been described to occur following a mechanical compression of blood vessels by rapidly proliferating cancer cells [27].…”

Imaging tumor hypoxia: Blood-borne delivery of imaging agents is fundamentally different in hypoxia subtypes

“…Perfusion-dependent nutrient supply, delivery of anticancer agents (e.g., chemotherapeutic drugs, antibodies or immune cells) or diagnostic agents for tumor imaging can be impaired or abolished or may not be a®ected, depending on the underlying causative mechanism (see Table 2). 18 A schematic representation of the radial di®usion distances for oxygen and hypoxia tracers drops within a tumor cell cylinder around a straight microvessel is exemplarily shown for two types of chronic hypoxia in Fig. 2. …”

“…In analogy with Table 2, relevant delivery conditions for blood-borne agents are listed for the subtypes of acute hypoxia in Table 3. 18 Examples for two types of acute hypoxia (temporary vascular occlusion and transient plasma°ow only) are shown in Fig. 3.…”

“…New highly conformal and accurate radiation technology, such as intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT) make these methods feasible. 7 In order to detect and quantify tumor hypoxia and to assess its topological distribution within a tumor as well as changes in extent (severity) and location upon radiotherapy, the contenders for human application are repeated, sequential PET measurements using 18 FMISO, 18 FAZA, 18 FEF5 and 64 CuATMS. [7][8][9][10][11] For detection, all techniques mentioned require injection of the respective exogenous marker (imaging agent).…”

Circulating Tumor Cells in the Parallel Invasion Model Supporting Early Metastasis

“…In accordance with the parallel metastasis model, the first CTCs are released at a small tumor size following the first angiogenic switch. [13] Oxygen can diffuse over a distance of approximately 200 µm and beyond that distance vessels are needed for respiration [86]. Thus, it may be not possible in patients to identify the first step of metastasis and isolate the respective cancer cells.…”