Tumor Hypoxia and Malignant Progression
Introduction
Cells exposed to hypoxic conditions respond by reducing their overall protein synthesis by approximately 50%. Abundant evidence suggests that hypoxia (i.e., the state of oxygen deficiency) can slow down or even completely inhibit (tumor) cell proliferation in vitro.1, 2 Furthermore, sustained hypoxia can change the cell cycle distribution and the relative number of quiescent cells, which in turn can lead to alterations in the response to radiation and many chemotherapeutic agents. The degree of inhibition depends on the severity and duration of hypoxia, on the coexistence of other microenvironmental inadequacies (e.g., acidosis, glucose depletion), and on the cell line investigated. The response of cells exposed to hypoxia in terms of the cell cycle is in most cases a G1⧸S-phase arrest. Hypoxia levels necessary to induce a disproportionate lengthening of G1 or an accumulation of cells in this cycle phase are in the range of 0.2–1 mm Hg.3, 4 Above this “hypoxic threshold” the environmental O2 status appears to have only negligible effects on the proliferation rate. Under anoxia, most cells undergo immediate arrest in whichever phase of the cell cycle they are in.
In addition to hypoxia-mediated changes in tumor cell proliferation, hypoxia can induce programmed cell death (apoptosis) both in normal and in neoplastic cells.5 p53 accumulates in cells under hypoxic conditions and induces apoptosis involving Apaf-1 and caspase-9 as important downstream effectors.6 However, hypoxia also initiates p53-independent apoptosis pathways, including those involving genes of the BCL-27 family and others.8 Below a critical energy state, hypoxia⧸anoxia may result in necrotic cell death, a phenomenon seen in many human tumors and experimental tumor models. Hypoxia-induced proteome changes leading to cell cycle arrest, differentiation, apoptosis, and necrosis may explain delayed recurrences, dormant micrometastases,9, 10 and growth retardation in large tumor masses.11
In contrast, hypoxia-induced proteome and⧸or genome changes in the tumor and⧸or stromal cells may promote tumor progression via mechanisms enabling cells to overcome nutritive deprivation, to escape from the “hostile” environment, and to favor unrestricted growth.
Sustained hypoxia in a growing tumor may also lead to cellular changes that can result in a more clinically aggressive phenotype.12, 13, 14 During the process of hypoxia-driven malignant progression, tumors may develop an increased potential for local invasive growth,15, 16 perifocal tumor cell spreading,12, 17 and regional and distant tumor cell metastasis.14, 18 Likewise, an intrinsic resistance to radiation and other cancer treatments may be enhanced, resulting in a poor prognosis.19, 20
This article presents current information from experimental and clinical studies, which illustrates the interaction between tissue hypoxia and the phenomenon of malignant progression. As more and more evidence concerning the fundamental biologic and clinical importance of tumor hypoxia emerges, data described here should be considered partially selective and therefore can only represent a “snapshot” of currently available data.
Section snippets
Evidence and Characterization of Tumor Hypoxia
Clinical investigations carried over since the late 1980s have clearly demonstrated that the prevalence of hypoxic tissue areas [i.e., areas with O2 tensions (pO2 values) ≤2.5 mm Hg] is a characteristic pathophysiological property of locally advanced solid tumors and that such areas have been found in a wide range of human malignancies: cancers of the breast, uterine cervix, head and neck, rectum and pancreas; brain tumors, soft tissue sarcomas, and malignant melanomas.19, 20, 21, 22
Evidence
Pathogenesis of Tumor Hypoxia
Hypoxic (or anoxic) areas arise as a result of an imbalance between the supply and the consumption of oxygen (Fig. 2). Whereas in normal tissues or organs the O2 supply matches the metabolic requirements, in locally advanced solid tumors the O2 consumption rate of neoplastic as well as stromal cells may outweigh an insufficient oxygen supply and result in the development of tissue areas with very low O2 levels.
Major pathogenetic mechanisms involved in the emergence of hypoxia in solid tumors
Methods for Detection of Tumor Hypoxia
Assessment of the tumor oxygenation status by invasive and noninvasive procedures has been reviewed previously1, 24, 25, 26, 27 (Table I). So far, the most direct method for identifying hypoxia in solid tumors is the polarographic measurement of O2 partial pressure (pO2) distributions using O2-sensitive microsensors. With this invasive microtechnique, frequency distributions of intratumor pO2 values can be obtained with a relatively high spatial resolution. However, it has the disadvantage that
Role of Hypoxia in Malignant Progression
When tumors develop, they often become more malignant with time, a process termed tumor progression. Substantial new data suggest that tumor hypoxia or anoxia (i.e., no measurable oxygen) and the HIF system are greatly involved in processes conferring a growth advantage to tumor cells and the development of a more malignant phenotype.1, 34, 35, 36, 37, 38 Depending on the level and (perhaps) duration of hypoxia, three mechanisms may be involved in hypoxia-induced tumor propagation: alterations
Acknowledgements
We thank Dr. Debra Kelleher and Dr. Cornelia Leo for critical reading and editorial help.
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