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Review
. 2024 Feb 22;16(5):890.
doi: 10.3390/cancers16050890.

Blood Vessel-Targeted Therapy in Colorectal Cancer: Current Strategies and Future Perspectives

Anne Jacobsen  1   2   3 , Jürgen Siebler  2   4 , Robert Grützmann  2   3 , Michael Stürzl  1   2 , Elisabeth Naschberger  1   2
Affiliations
Review

Blood Vessel-Targeted Therapy in Colorectal Cancer: Current Strategies and Future Perspectives

Anne Jacobsen et al. Cancers (Basel). .

Abstract

The vasculature is a key player and regulatory component in the multicellular microenvironment of solid tumors and, consequently, a therapeutic target. In colorectal carcinoma (CRC), antiangiogenic treatment was approved almost 20 years ago, but there are still no valid predictors of response. In addition, treatment resistance has become a problem. Vascular heterogeneity and plasticity due to species-, organ-, and milieu-dependent phenotypic and functional differences of blood vascular cells reduced the hope of being able to apply a standard approach of antiangiogenic therapy to all patients. In addition, the pathological vasculature in CRC is characterized by heterogeneous perfusion, impaired barrier function, immunosuppressive endothelial cell anergy, and metabolic competition-induced microenvironmental stress. Only recently, angiocrine proteins have been identified that are specifically released from vascular cells and can regulate tumor initiation and progression in an autocrine and paracrine manner. In this review, we summarize the history and current strategies for applying antiangiogenic treatment and discuss the associated challenges and opportunities, including normalizing the tumor vasculature, modulating milieu-dependent vascular heterogeneity, and targeting functions of angiocrine proteins. These new strategies could open perspectives for future vascular-targeted and patient-tailored therapy selection in CRC.

Keywords: aflibercept; angiocrine; antiangiogenic treatment; bevacizumab; cancer; colorectal cancer; endothelial cells; fruquintinib; ramucirumab; regorafenib; tumor microenvironment; vascular heterogeneity; vasculature.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
The tumor-related vascular structure and hierarchy determine the surgical resection strategy used for colorectal cancer. Surgical preparation after right hemicolectomy with complete mesocolic excision because of cecal carcinoma (circle). Central ligation of the ileocolic vessels (artery and vein) and the right colic artery (dashed lines) ensures resection of the regional lymph nodes, which is well known to improve survival.
Figure 2
Figure 2
Different types of vessels are present in human colorectal cancer tissues. In human CRC, blood vessels can be labeled using the markers CD31 or vWF. Lymphatic vessels may be stained with LYVE-1 or podoplanin. Arteries and veins can be differentiated by labeling using the artery marker ephrinB2. This may be complemented by morphological differentiation of arteries (A) and veins (V) together with analysis of milieu-dependent expression of vessel markers such as SPARCL1. CD31, vWF, LYVE-1 and podoplanin panels: 25x objective; ephrinB2 and SPARCL1 panels: scale bars corresponding to 50 µm. The vWF panel is modified from Schellerer et al., Lab Invest 2007 [97].
See this image and copyright information in PMC

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