Overview on the Different Patterns of Tumor Vascularization.

Domenico Ribatti,Francesco Pezzella

doi:10.3390/cells10030639

Domenico Ribatti, Francesco Pezzella

Open Access

https://doi.org/10.3390/cells10030639

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Abstract

Angiogenesis is a crucial event in the physiological processes of embryogenesis and wound healing. During malignant transformation, dysregulation of angiogenesis leads to the formation of a vascular network of tumor-associated capillaries promoting survival and proliferation of the tumor cells. Starting with the hypothesis formulated by Judah Folkman that tumor growth is angiogenesis-dependent, this area of research has a solid scientific foundation and inhibition of angiogenesis is a major area of therapeutic development for the treatment of cancer. Over this period numerous authors published data of vascularization of tumors, which attributed the cause of neo-vascularization to various factors including inflammation, release of angiogenic cytokines, vasodilatation, and increased tumor metabolism. More recently, it has been demonstrated that tumor vasculature is not necessarily derived by endothelial cell proliferation and sprouting of new capillaries, but alternative vascularization mechanisms have been described, namely vascular co-option and vasculogenic mimicry. In this article, we have analyzed the mechanisms involved in tumor vascularization in association with classical angiogenesis, including post-natal vasculogenesis, intussusceptive microvascular growth, vascular co-option, and vasculogenic mimicry. We have also discussed the role of these alternative mechanism in resistance to anti-angiogenic therapy and potential therapeutic approaches to overcome resistance.

Highlights

In 1787, the concept of angiogenesis was introduced by John Hunter, the founder of scientific surgery, describing the process through which new blood vessels arise from preexisting ones, [1,2,3]
The first historical description of blood vessels related to cancer is commonly accredited to Galen of Pergamon (AD 129-c. 200/c. 216) in his treaty On abnormal swellings: “Whenever black bile attacks the flesh, because it is corrosive, it eats into the surrounding skin producing an ulcer
This paper introduced the term anti-angiogenesis to mean the prevention of new vessel sprout from being recruited by a tumor

Summary

Background

In 1787, the concept of angiogenesis was introduced by John Hunter, the founder of scientific surgery, describing the process through which new blood vessels arise from preexisting ones, [1,2,3]. The conclusion that tumor growth relies on sprouting angiogenesis [9] was largely based on in vitro experiments and animal models where the experiments were conducted in relatively avascular sites, such as the cornea and the ear of the rabbit Despite this nonphysiological condition (most cancers arise in well vascularized tissues) these experiments were regarded as a convincing proof of concept. In 1943–45, Algire and co-workers [13,14,15] used a transparent chamber implanted in a cat’s skin to study the vasoproliferative reaction secondary to the implantation of neoplastic tissues, and showed that the response induced by tumor tissues was more substantial and earlier than that induced by normal tissues They quantified the number of blood vessels and demonstrated that the tumor growth is closely related to the development of an intrinsic vascular network [13,14,15]. New blood vessels were formed very likely through the release of a diffusible factor that could pass through the pores

Isolation of the First Tumor Angiogenic Factor

Tumor Angiogenesis in Human Tumor Progression as a Prognostic Indicator

Vasculogenic Mimicry

Intussusceptive Angiogenesis

Findings

Concluding Remarks