Growth Patterns and Angiogenesis in Liver Metastases

The liver is a densely vascularized organ that frequently hosts metastases of colorectal and breast adenocarcinomas. Hypothetically, tumors that would be able to preserve this vasculature, well adapted to the high metabolic needs of physiological liver function, would not necessarily induce hypoxia-driven angiogenesis. Also, the gradient of angio-genic factors necessary for endothelial cell migration and proliferation might be diluted by the high vascular flow. Comparison of the histology of liver metastases in breast cancer and colorectal cancer patients has revealed a growth pattern that preserves the liver architecture and thus co-opts the preexisting sinusoidal blood vessels ([4]; Stessels F. et al., 2004). This growth pattern was expressed in nearly all breast cancer liver metastases (43/45) and in only a minority of the colorectal cancer liver metastases (9/28), and was characterized by tumor cells replacing the hepato-cytes in the liver plates without inducing inflammation or fibrosis (Figure 2). In this "replacement" growth pattern, the endothelial cells of the coopted sinusoidal blood vessels lost their constitutive LYVE-1 expression and started to express CD34, suggesting paracrine interactions between coopted endothelial cells and tumor cells. The endothelial cell proliferation fraction in this growth pattern, as a measure of ongoing angiogenesis, was low (about 3%) and only a small minority of the breast cancer liver

Figure 2 Replacement growth pattern in a liver metastasis of a breast adenocarcinoma. The tumor cells (left) are replacing the hepatocytes in the liver plates (right), thereby coopting the sinusoidal blood vessels. There is close apposition of tumor cells and hepatocytes at the tumor-liver interface (arrows) without induction of inflammation or fibrosis.

Figure 2 Replacement growth pattern in a liver metastasis of a breast adenocarcinoma. The tumor cells (left) are replacing the hepatocytes in the liver plates (right), thereby coopting the sinusoidal blood vessels. There is close apposition of tumor cells and hepatocytes at the tumor-liver interface (arrows) without induction of inflammation or fibrosis.

metastases with a replacement growth pattern expressed the hypoxia marker CA IX or had fibrin depositions at the tumor-liver interface (Table II). Probably, the well-described mechanisms of invasive tumor growth, such as fibroblast-myofibroblast transdifferentiation, TGFb pathways, proinflammatory signaling, hyaluronic acid action, and hypoxia-responsive gene activation, are not involved. The search for gene sets that are responsible for the pheno-type of nonangiogenesis-dependent colonization of a distant site is ongoing. Selective induction of apoptosis in hepatocytes at the interface by tumor cells might be one of the mechanisms of growth of blood-vessel-coopting metastases. The other growth patterns in the liver were characterized by destruction of the architecture of the liver parenchyma and were associated with desmoplasia and new blood vessel formation. The metastases were (desmoplastic growth pattern) or were not (pushing growth pattern) surrounded by a fibrotic capsule.

The consequences of this heterogeneity of human liver metastases are the limited value of model systems that selectively reproduce the well-studied angiogenesis-dependent growth of metastases and the difficulties in analyzing the results of clinical trials applying biomodulatory drugs. Imaging of the vascular flow and leakage by contrast-enhanced CT or MR might be helpful in selecting patients with angiogenic versus nonangiogenic liver metastases. The existence of different growth patterns also stresses the superior value of the endothelial cell proliferation (ECP) fraction for angiogenesis quantification compared to microvessel density [1]. Liver metastases with a replacement growth pattern indeed have a high microvessel density as a result of cooption of the liver vasculature but have a low ECP due to lack of ongoing angiogenesis.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

Get My Free Ebook


Post a comment