Functional imaging of colorectal cancer angiogenesis

doi:10.1016/S1470-2045(07)70075-X

The Lancet Oncology

Volume 8, Issue 3, March 2007, Pages 245-255

https://doi.org/10.1016/S1470-2045(07)70075-X Get rights and content

Summary

Angiogenesis is a key factor in the growth and dissemination of colorectal cancer, with significant implications for its clinical management. Previous trials have provided proof-of-principle that inhibition of angiogenesis has the potential to enhance the effectiveness of treatment for this disease. Characterisation of the angiogenic status of the tumour on an individual patient basis could allow for a more targeted approach to treatment. In vivo imaging techniques that assess tumour microvessel function have the potential to improve the management of treatment for patients with colorectal cancer. This review focuses on MRI and CT assessment of colorectal cancer angiogenesis. We discuss the effects that these two techniques have had in the assessment of this disease, including tumour staging and therapeutic assessment. Their comparability with other imaging techniques, in particular ultrasound, and their limitations are also addressed.

Introduction

Neovascularisation is an essential process for colorectal tumour growth and dissemination.¹ Angiogenesis, the formation of new vessels by sprouting of endothelial cells, and vasculogenesis, de novo vascular formation from precursor endothelial cells from bone marrow, are the main mechanisms by which this occurs. Neovascularisation arises early in the adenoma–carcinoma sequence, via upregulation of vascular endothelial growth factor (VEGF), possibly related to the K-RAS mutation,² which is present in 24% of adenomas.³ Tumour angiogenesis is characterised structurally by abnormal blood vessels that are thin, fragile, tortuous, and hyperpermeable as a result of an incomplete endothelium and a relative absence of smooth muscle and pericyte coverage compared with normal blood vessels. These vessels lack the usual vessel hierarchy, by having a chaotic, heterogeneous intratumoral distribution. This distribution consists of areas of low vascular density mixed with regions of high angiogenic activity, with a general decline in vessel density towards the tumour centre in colorectal adenomas and carcinomas.4, 5, 6, 7 Functionally, these vessels differ from normal vessels, with evidence of arteriovenous shunting, intermittent flow, or even reversal of flow because of acute vascular collapse, with raised tumour interstitial pressure, and increased haematocrit.

The level of angiogenic activity in colorectal tumours can be a predictor of patient survival. Clinical trials have established that, in first-line and second-line treatment of metastatic colorectal cancer, the addition of the vascular VEGF-directed antibody, bevacizumab, to chemotherapy, significantly prolongs survival compared with chemotherapy alone.8, 9 Oral agents that target VEGF-receptor signalling have not, as yet, proved to be efficacious in phase III trials in advanced colorectal cancer. A better understanding of the processes involved in colorectal tumour angiogenesis is clearly important, because the number of antivascular compounds entering clinical trials is constantly increasing. In vivo imaging techniques that assess tumour microvessel functionality, therefore, have the potential to affect the management of treatment for patients with colorectal cancer. The ability of dynamic contrast-enhanced MRI (DCE-MRI) and dynamic contrast-enhanced CT, also called perfusion CT, to image functional vascular changes related to angiogenesis will be discussed in this review (figure 1). Focus will be made on the clinical usefulness of DCE-MRI and perfusion CT, their comparability with other imaging techniques, such as ultrasound, and their limitations. However, in view of the scarcity of published work referring specifically to colorectal-cancer angiogenesis in people, the use of perfusion and blood-volume tracers, such as ¹⁵O-labelled water or carbon monoxide positron emission tomography (PET), will not be discussed in this review.

Section snippets

Colorectal cancer angiogenesis

New vessel formation results from a cascade of events that involve multiple cytokines and cell types. Angiogenesis begins when the tightly regulated dynamic equilibrium of proangiogenic and antiangiogenic factors is disturbed. This disturbance can be in response to tumour hypoxia, glucose deprivation, secretion of growth factors or inflammatory proteins by tumour cells, mechanical stress, or by genetic changes involving activation of oncogenes or inactivation of tumour-suppressor genes.¹⁰ The

Dynamic contrast-enhanced MRI

DCE-MRI, using low-molecular-weight (<1 kDa) gadolinium-based paramagnetic contrast media, is an attractive technique for assessing the vascular physiology of tumours, by combining good anatomical detail with the ability to quantify vascular parameters. The rate at which contrast medium passes from the intravascular space to the extravascular extracellular space and then back to the intravascular space over time after bolus injection, differs between normal tissue and tumour tissue and can be

Detection and staging of colorectal cancer angiogenesis by imaging

Although MRI is an established imaging technique for staging rectal cancers, little attention has been paid to the usefulness of DCE-MRI for the detection and staging of primary disease, and inadequate data are available for perfusion CT and doppler ultrasound. Preliminary data suggest that perfusion CT can potentially improve the detection of cancer in patients with diverticular disease.⁷² Up to 30% of colon cancers are coincident with diverticular disease, and distinction can be difficult on

Antiangiogenic and vascular disruptive agents

Proof-of-principle clinical trials have shown that inhibition of angiogenesis has the potential to enhance the effectiveness of treatment for colorectal cancer.8, 81 These studies have shown that: (1) in both first-line and second-line treatment of metastatic colorectal cancer, the addition of the VEGF–directed antibody, bevacizumab, to chemotherapy significantly prolongs survival compared with chemotherapy alone; (2) bevacizumab has minimum activity as a single agent; and (3) oral agents

Future for imaging

Successes of antiangiogenic drug treatment in colorectal cancer, and a more individualised approach to drug treatment, have brought new challenges for imaging, with a shift from a morphological approach to one that is more functional. DCE-MRI and perfusion CT have great potential, not just for guiding treatment decisions and affecting treatment outcome, but, more fundamentally, for informing on tumour biology. Undoubtedly, DCE-MRI and perfusion CT techniques will continue to develop as

Conclusion

This review has focused on the more established low-molecular-weight DCE-MRI and CT imaging techniques for the functional assessment of colorectal angiogenesis. However, there are other developing approaches, such as DCE-MRI and CT with macromolecular contrast agents, imaging of hypoxia with blood-oxygen-level-dependent MRI, and PET imaging with vascular and hypoxia tracers such as ¹⁵[O]-H₂O PET and ¹⁵[O]-CO PET; [¹⁸F]fluoromisonidazole PET and Cu-ATSM PET are also other approaches. These

Search strategy and selection criteria

Data for this review were identified by searches of PUBMED using the search terms “colon”, “rectum”, “colorectal cancer”, “cancer/tumour”, “angiogenesis”, “neovascularisation”, “imaging”, “dynamic MRI”, “DCE-MRI”, “functional CT”, “perfusion CT”, “ultrasound”, “Doppler”, “positron emission tomography”, “PET”, “PET-CT”, “contrast agents”, “FDG-PET”, “fluorodeoxyglucose”, “FLT”, “fluorothymidine”, “H20 PET”, “11 carbon monoxide PET”. Only papers published in English between 1990 and 2006

Glossary

T1-relaxation time: Time taken for protons to return to their original magnetic alignment after disturbance by a radiofrequency pulse

T2* decay: A result of inhomogeneities in the magnetic field, which result in a more rapid loss of phase coherence than by T2 decay alone, which results from spin–spin energy transfer

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ReviewFunctional imaging of colorectal cancer angiogenesis

Summary

Introduction

Section snippets

Colorectal cancer angiogenesis

Dynamic contrast-enhanced MRI

Detection and staging of colorectal cancer angiogenesis by imaging

Antiangiogenic and vascular disruptive agents

Future for imaging

Conclusion

Search strategy and selection criteria

Glossary

Neoplasia

Eur J Surg Oncol

Eur J Cancer

Eur J Cancer

Cell

Int J Radiat Oncol Biol Phys

Lancet

Cancer Cell

Tumor angiogenesis: therapeutic implications

N Engl J Med

Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis

Cancer Res

K-ras gene mutation related to histological atypias in human colorectal adenomas

Biotech Histochem

3D microvascular architecture of pre-cancerous lesions and invasive carcinomas of the colon

Br J Cancer

Transport of molecules across tumor vasculature

Cancer Metastasis Rev

Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis

Curr Top Microbiol Immunol

Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies

Cancer Res

Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer

N Engl J Med

Lessons from phase III clinical trials on anti-VEGF therapy for cancer

Nat Clin Pract Oncol

Fundamental concepts of the angiogenic process

Curr Mol Med

Vascular endothelial growth factor secretion by tumor-infiltrating macrophages essentially supports tumor angiogenesis, and IgG immune complexes potentiate the process

Cancer Res

Vascular endothelial growth factors C and D and lymphangiogenesis in gastrointestinal tract malignancy

Br J Cancer

Concurrent expression of angiogenic growth factors and neovascularization during tumourigenesis in colorectal carcinoma patients

Acta Oncol

Clinical significance of angiogenic factor expression at the deepest invasive site of advanced colorectal carcinoma

Oncology

Clinical significance of vascular endothelial growth factor C expression and angiogenesis at the deepest invasive site of advanced colorectal carcinoma

Oncology

VEGF expression in the colorectal adenoma-carcinoma sequence

Oncol Res

Implication of vascular endothelial growth factor p53 status for angiogenesis in noninvasive colorectal carcinoma

Cancer

Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature

Br J Cancer

Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node negative colon cancer

Arch Surg

Coexpression of VEGF-C and Cox-2 in human colorectal cancer and its association with lymph node metastasis

Dis Colon Rectum

Microvessel quantification and its possible relation with liver metastasis in colorectal cancer

Cancer

Angiogenesis as an unfavorable prognostic factor in human colorectal cancer

Cancer

Tumor angiogenesis and rectal carcinoma

Dis Colon Rectum

Tumor angiogenesis as predictor of recurrence and survival in patients with node negative colon cancer

Ann Surg

Tumor angiogenesis and mode of metastasis in patients with colorectal cancer

Cancer Res

Tumor angiogenesis as a prognostic predictor in colorectal carcinoma with special reference to mode of metastasis and recurrence

Oncology

Prospective study of intratumoral microvessel density, p53 expression, and survival in colorectal cancer

Br J Cancer

Angiogenesis as a prognostic indicator of survival in non-small cell lung cancer

J Natl Cancer Inst

High tumour angiogenesis is associated with poorer survival in carcinoma of the cervix treated with radiotherapy

Clin Cancer Res

Tumor angiogenesis and metastasis- correlation in invasive breast cancer

N Eng J Med

Review
Functional imaging of colorectal cancer angiogenesis