Tumor microenvironmental physiology and its implications for radiation oncology

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Abstract

The microenvironmental physiology of tumors is uniquely different from that of normal tissues. It is characterized, inter alia, by O2 depletion (hypoxia, anoxia), glucose and energy deprivation, high lactate levels, and extracellular acidosis, parameters that are anisotropically distributed within the tumor mass. This hostile microenvironment is largely dictated by the abnormal tumor vasculature and heterogeneous microcirculation. Hypoxia and other hostile microenvironmental parameters are known to directly or indirectly confer resistance to irradiation leading to treatment failure. Hypoxia directly leads to a reduced “fixation” of radiation-induced DNA damage. Indirect mechanisms include a restrained proliferation, changes in gene expression and alterations of the proteome (eg, elevated activity of DNA-repair enzymes and resistance-related proteins, increased transcription of growth factors), and genomic changes (genomic instability leading to clonal heterogeneity and selection of resistant clonal variants). These changes, caused by the hostile microenvironment, can favor tumor progression and acquired treatment resistance, both resulting in poor clinical outcome and prognosis. Pretreatment assessment of critical microenvironmental parameters is therefore needed to allow the selection of patients who could benefit from special treatment approaches (eg, hypoxia-targeting therapy). Because of a relatively high risk of local relapse or distant metastasis, patients with hypoxic and/or “high-lactate” tumors should undergo close surveillance.

Section snippets

Tumor vascularity and blood flow

As already mentioned, newly formed microvessels in most solid tumors do not conform to the normal morphology of the host tissue vasculature (Fig 1). Microvessels in solid tumors exhibit a series of severe structural and functional abnormalities. They are often dilated, tortuous, elongated, and saccular. There is significant arteriovenous shunt perfusion accompanied by a chaotic vascular organization that lacks any regulation matched to the metabolic demands or functional status of the tissue.

Fluid pressure and convective currents in the interstitial space of tumors

The growing tumor produces new, often abnormally leaky microvessels, but is unable to form its own functioning lymphatic system. As a result of this and because of a large hydraulic conductivity, there is a significant bulk flow of free fluid in the interstitial space. Whereas in the normal tissue, convective currents in the interstitial compartment are estimated to be about 0.5% to 1 % of plasma flow, in human cancers, interstitial water flux can reach 15 % of the respective plasma flow (Fig 3)

Evidence, characterization, and pathogenesis of tumor hypoxia

Clinical investigations carried out over the last 15 years have clearly shown that the prevalence of hypoxic tissue areas (ie, 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 including cancers of the breast, uterine cervix, vulva, head & neck, prostate, rectum, pancreas, brain tumors, soft-tissue sarcomas, and malignant melanomas.8, 16, 22, 23

Tumor pH

Under many conditions, it has been confirmed that the intracellular pH (pHi) in tumor cells is neutral to alkaline as long as tumors are not oxygen and energy deprived.2, 25 Tumor cells have efficient mechanisms for exporting protons into the extracellular space, which represents the acidic compartment in tumors. Cellular pH regulation is mainly accomplished by a Na+/H+ exchanger, which can be activated by a series of growth factors also involved in tumor angiogenesis.26 For this reason, a pH

The “crucial P’s” characterizing the hostile metabolic microenvironment of solid tumors

Applying quantitative imaging bioluminescence, Walenta et al29, 30, 31 have provided clinical evidence that lactate accumulation mirrors malignant potential in squamous cell carcinomas of the uterine cervix and of the head and neck and in colorectal adenocarcinomas. Concentrations of lactate in viable tumor areas exhibited pronounced intra- and intertumor differences compared with glucose and adenosine triphosphate, although tumor glucose levels correlated inversely with lactate concentrations

The Janus face of tumor hypoxia

Cells exposed to hypoxic conditions respond by reducing their overall protein synthesis, which leads to restrained proliferation and eventually to cell death. There is abundant evidence suggesting that hypoxia can slow down or even completely inhibit (tumor) cell proliferation in vitro.35, 36 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

Tumor hypoxia as an obstacle in radiotherapy

Tumor hypoxia (and other parameters defining the hostile tumor microenvironment) may present a severe problem for radiation therapy (X- and γ-radiation) because radiosensitivity rapidly decreases when the O2 partial pressure in a tumor is less than 25 to 30 mm Hg. Hypoxia-associated resistance to photon radiotherapy is multifactorial (Fig 5). The presence of molecular oxygen can prevent repair of the DNA damage (ie, O2 “fixes” the DNA damage [O2 makes the DNA damage permanent]). Thus, because

Microenvironmental parameters as prognostic factors

Because of the association between tumor hypoxia, malignant progression, and treatment failure, tumor hypoxia has proven to be an independent, powerful prognostic factor for local control, overall, and disease-free survival. An adverse prognostic impact of tumor hypoxia in various tumor entities—among them cancers of the uterine cervix, head and neck, and soft-tissue sarcomas—has repeatedly been shown.23, 50 In cervical carcinomas, this impact on prognosis was independent of treatment modality,

Conclusion

Pretreatment assessment of critical microenvironmental parameters is needed to allow the selection of cancer patients who could benefit from special treatment forms (eg, hypoxia targeting, suppression of hypoxia-inducible transcription). Because of the relatively high risk of local relapse or distant metastasis, patients with hypoxic and/or “high-lactate” tumors should undergo close surveillance.

Acknowledgements

The valuable assistance of Debra K. Kelleher in preparing this manuscript is greatly appreciated.

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