The pathophysiology of the tumor microenvironment: Coping with hostile conditions and spatio-temporal heterogeneities
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1
Klinikum rechts der Isar, Klinik und Poliklinik für Strahlentherapie, TU München, Department of Radiotherapy and Radiooncology, Germany
Background. The tumor microenvironment (i.e., the sophisticated, co-operative “network” of different components, their multiple functions and activities, and complex interactions between all types of cells, the acellular matrix and soluble factors within malignant tumors) is known to be a key player for translational adaptive changes in tumor metabolism, for tumor growth, malignant progression (e.g., local spread, distant metastasis), the development of acquired treatment resistance, and finally for poor patient prognosis [1].
Aberrant microvascular functions are pivotal factors for the development of an adverse pathophysiological microenvironment. Pathophysiological conditions related to the newly formed, mostly irregular and premature vascular network, as well as a heterogeneous (both spatially and temporally, “4D- heterogeneity”) and inadequate microcirculation (blood flow) substantially contribute to the development of a hostile microenvironment. Besides the abnormal microvascular network and the heterogeneous, aberrant microcirculation, high vascular permeability, expansion of the interstitial space, high interstitial fluid pressure (as a result of vascular hyperpermeabilty and lack of functioning lymphatics) may contribute to the setting of the pathophysiological microenvironment [2].
Major pathophysiological features of the tumor microenvironment: The consequences of the irregular structure and function of the tumor microcirculation and the flow-related, adverse microenvironment include: (a) inadequate oxygen supply, multifactorial pathogenesis of tumor hypoxia and anoxia, translational hypoxia-response processes (preferentially via activation of the HIF-system) and alterations in the cellular redox state, (b) adaptive changes in metabolism (metabolic reprogramming), upregulation of glycolysis capacity and lactate accumulation, (c) extracellular acidosis with a reversed pH gradient across the cell membrane as compared to normal cells, (d) increased intratumor carbon dioxide tensions (hypercapnia) and bicarbonate depletion, (e) nutrient deprivation and energy depletion, and (f) ATP hydrolysis and adenosine accumulation [3].
Conclusions. The irregular structure and function of the tumor microcirculation results in self-perpetuating hostile pathophysiological tumor microenvironments with physiological, metabolic, biophysical and physico-biochemical traits, which are uniquely different to that of normal tissues. Many traits are known to trigger translational “maladaptations” favorable to survival under these conditions, can lead to growth advantages over non-adapted cells, may favor the expansion of aggressive and therapy-resistant tumor cells through selection and clonal expansion, and may promote tumor stem cell maintenance.
References
[1] Vaupel P (2004) Semin. Radiat. Oncol. 14:198.
[2] Vaupel P (2008) Oncologist 13, Suppl.3, 21.
[3] Vaupel P et al (2004) Methods Enzymol. 381:335
Keywords:
Tumor Microenvironment,
spatio-temporal heterogeneities,
tumor metabolism,
therapy-resistant tumor cells,
extracellular acidosis,
pH gradient
Conference:
4th Annual Meeting of the International Society of Proton Dynamics in Cancer, Garching, Germany, 10 Oct - 12 Oct, 2013.
Presentation Type:
Abstract
Topic:
4. pH and energy metabolism
Citation:
Vaupel
P
(2014). The pathophysiology of the tumor microenvironment: Coping with hostile conditions and spatio-temporal heterogeneities.
Front. Pharmacol.
Conference Abstract:
4th Annual Meeting of the International Society of Proton Dynamics in Cancer.
doi: 10.3389/conf.fphar.2014.61.00048
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Received:
16 Dec 2013;
Published Online:
07 Feb 2014.
*
Correspondence:
Prof. Peter Vaupel, Klinikum rechts der Isar, Klinik und Poliklinik für Strahlentherapie, TU München, Department of Radiotherapy and Radiooncology, Munich, Germany, vaupel@uni-mainz.de