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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