Abstract
The process of tumor neoangiogenesis plays a central role in the growth and spread of tumors. It is currently a leading theme in oncology, and many new drugs targeting the tumor neoangiogenic process are under development. Expanding tumors become hypoxic and tumor cells express transcription factors, such as the hypoxia-inducible factor (HIF), which induce the release of proangiogenic growth factors such as vascular endothelial growth factors (VEGF) and transforming growth factors that promote the formation of new capillaries by recruiting, activating, and stimulating endothelial cells. Activated endothelial cells secrete matrix metalloproteases, which degrade the basement membrane and the extracellular matrix, and adhesion receptors such as integrins αvβ3, which allow their migration into the extracellular matrix toward the tumor cells. The newly grown vessels are immature and differ from normal capillaries. They are tortuous and irregular, resulting in poorly efficient perfusion, they are leaky (especially to macromolecules), and they are independent of the normal mechanisms of regulation of the capillary blood flow. Moreover, tumor microcirculation is heterogeneous. Evaluation of angiogenesis can be used as a prognostic marker to evaluate the aggressiveness of tumor and as a potential predictive marker of antiangiogenic treatment response. Histopathologic techniques of microvascular density indexes require invasive tissue sampling and need to be standardized. Hemodynamic characteristics of immature neovessels can be noninvasively assessed by dynamic contrast-enhanced magnetic resonance imaging or computed tomography. Tissue enhancement depends on arterial input function, kinetic of distribution of blood into the capillary bed, leakage across the capillary walls, and volume of the interstitial space. Pharmacodynamic models allow the evaluation of microvascular parameters of tissue blood flow, tissue blood volume, tissue interstitial volume, mean transit time, and permeability by surface of capillary wall. Methods based on dynamic contrast enhancement have been shown to correlate with conventional outcome methods such as histopathologic studies and survival. Radiologists must be convinced that, by using this emerging and promising approach, it is becoming possible to gain functional information during routine tumor imaging.
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References
Folkman J (1990) What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82:4–6
Brasch R, Turetschek K (2000) MRI characterization of tumors and grading angiogenesis using macromolecular contrast media: status report. Eur J Radiol 34:148–155
Griebel J, Mayr NA, de Vries A, et al. (1997) Assessment of tumor microcirculation: a new role of dynamic contrast MR imaging. J Magn Reson Imaging 7:111–119
Neeman M (2000) Preclinical MRI experience in imaging angiogenesis. Cancer Metastasis Rev 19:39–43
Buckley DL, Roberts C, Parker GJ, et al. (2004) Prostate cancer: evaluation of vascular characteristics with dynamic contrast-enhanced T1-weighted MR imaging—initial experience. Radiology 233:709–715
Miles KA (2002) Functional computed tomography in oncology. Eur J Cancer 38:2079–2084
Lee TY, Purdie TG, Stewart E (2003) CT imaging of angiogenesis. Q J Nucl Med 47:171–187
Cuenod C, Leconte I, Siauve N, et al. (2001) Early changes in liver perfusion caused by occult metastases in rats: detection with quantitative CT. Radiology 218:556–561
Ribatti D, Vacca A, Dammacco F (2003) New non-angiogenesis dependent pathways for tumor growth. Eur J Cancer 39:1835–1841
Barentsz JO, Berger-Hartog O, Witjes JA, et al. (1998) Evaluation of chemotherapy in advanced urinary bladder cancer with fast dynamic contrast-enhanced MR imaging. Radiology 207:791–797
Padhani AR (2002) Functional MRI for anticancer therapy assessment. Eur J Cancer 38:2116–2127
Anderson H, Price P, Blomley M, et al. (2001) for the Cancer Research Campaign PK/PD Technologies Advisory Committee. Measuring changes in human tumour vasculature in response to therapy using functional imaging techniques. Br J Cancer 85:1085–1093
Pradel C, Siauve N, Bruneteau G, et al. (2003) Reduced capillary perfusion and permeability in human tumour xenografts treated with the VEGF signalling inhibitor ZD4190: an in vivo assessment using dynamic MR imaging and macromolecular contrast media. Magn Reson Imaging 21:845–851
Ribatti D, Vacca A, Dammacco F (2003) New non-angiogenesis dependent pathways for tumor growth. Eur J Cancer 39:1835–1841
Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186
Brahimi-Horn MC, Pouyssegur J (2005) The hypoxia-inducible factor and tumor progression along the angiogenic pathway. Int Rev Cytol 242:157–213
Latif F, Tory K, Gnarra J, et al. (1993) Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260:1317–1320
Haas TL, Madri JA (1999) Extracellular matrix-driven matrix metalloproteinase production in endothelial cells: implications for angiogenesis. Trends Cardiovasc Med 9:70–77
Liotta LA, Steeg PS, Stetler-Scevenson WG (1991) Cancer metastasis and angiogenesis; An imbalance of positive and negative regulation. Cell 64:327–336
Hwang R, Varner J (2004) The role of integrins in tumor angiogenesis. Hematol Oncol Clin North Am 18:991–1006,
Brooks PC, Dark. RA, Cheresh DA (1994) Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 264:569–571
Ribatti D (2004) The involvement of endothelial progenitor cells in tumor angiogenesis. J Cell Mol Med 8:294–300
Anderson SA, Glod J, Arbab AS, et al. (2005) Noninvasive MR imaging of magnetically labeled stem cells to directly identify neovasculature in a glioma model. Blood 105:420–425
Jain RK (1988) Determinants of tumor blood flow: a review. Cancer Res 15:2641–2658
Less JR, Posner MC, Skalak TC, et al. (1997) Geometric resistance and microvascular network architecture of human colorectal carcinoma. Microcirculation 4:25–33
Jain RK (1996) Delivery of molecular medicine to solid tumors. Science 271:1079–1080
Less JR, Skalak TC, Sevick EM, Jain RK (1991) Microvascular architecture in a mammary carcinoma: branching patterns and vessel dimensions. Cancer Res 51:265–273
Liotta LA, Kleinennan J, Saidel GM (1974) Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. Cancer Res 34:997–1004
Dvorak HF, Nagy JA, Dvorak JT, et al. (1988) Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules. Am J Pathol 133:95–109
Gasparini G, Weidner N, Bevilacqua P, et al. (1994) Tumor microvessel density, p53 expression, tumor size, and peritumoral lymphatic vessel invasion are relevant prognostic markers in node-negative breast carcinoma. J Clin Oncol 12:454–466
Miller JC, Pien HH, Sahani D, et al. (2005) Imaging angiogenesis: applications and potential for drug development. J Natl Cancer Inst 97:172–187
Fox SB, Harris AL (2004) Histological quantitation of tumour angiogenesis. APMIS 112:413–430
McDonald DM, Choyke PL (2003) Imaging of angiogenesis: from microscope to clinic. Nat Med 9:713–725
Tofts PS, Brix G, Buckley DL (1999) Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: standardized quantities and symbols. J Magn Reson Imaging 10:223–232
Buckley DL (2002) Uncertainty in the analysis of tracer kinetics using dynamic contrast-enhanced T1-weighted MRI. Magn Reson Med 47:601–606
Evelhoch JL (1999) Key factors in the acquisition of contrast kinetic data for oncology. J Magn Reson Imaging 10:254–259
Padhani AR, Neeman M (2001) Challenges for imaging angiogenesis. Br J Radiol 74:886–890
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Cuenod, C.A., Fournier, L., Balvay, D. et al. Tumor angiogenesis: pathophysiology and implications for contrast-enhanced MRI and CT assessment. Abdom Imaging 31, 188–193 (2006). https://doi.org/10.1007/s00261-005-0386-5
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DOI: https://doi.org/10.1007/s00261-005-0386-5