Blood-brain Barrier Remodeling during Brain Metastasis Formation.

Jagoda K Wrobel,Michal Toborek

doi:10.2119/molmed.2015.00207

Abstract

Our understanding of the process of metastatic progression has improved markedly over the past decades, yet metastasis remains the most enigmatic component of cancer pathogenesis. This lack of knowledge has serious health-related implications, since metastasis is responsible for 90% of all cancer-related mortalities. The brain is considered a sanctuary site for metastatic tumor growth, where the blood-brain barrier (BBB) and other components of the brain microenvironment, provide protection to the tumor cells from immune surveillance, chemotherapeutics and other potentially harmful substances. The interactions between tumor cells and the brain microenvironment, principally brain vascular endothelium, are the critical determinants in their progression toward metastasis, dormancy, or clearance. This review discusses current knowledge of the biology of metastatic progression, with a particular focus on the tumor cell migration and colonization in the brain.

Highlights

The term “cancer” is used to describe a heterogeneous group of more than 100 diseases, defined by dynamic changes in the genome that lead to uncontrolled cellular growth [1]. Behind cardiovascular disease, cancer is the second leading cause of death in the majority of developed countries, with foreseen increased incidence in low- and middle-income countries in the upcoming decades [2]
Increased activity of the PI3K-Akt pathway, a crucial regulator of cell survival and proliferation, has been reported in several tumor cell types, including melanoma and breast cancer cells metastasizing to the brain [51,52,53]
Within metastatic breast cancer cells, several targets have been identified as mediators that promote tumor cell migration through the blood–brain barrier (BBB), including cyclooxygenase-2 (COX2), the epidermal growth factor receptor (EGFR) ligand HBEGF and α-2,6-sialyltransferase 5 (ST6GALNAC5) [65,66]

Summary

INTRODUCTION

The term “cancer” is used to describe a heterogeneous group of more than 100 diseases, defined by dynamic changes in the genome that lead to uncontrolled cellular growth [1]. Behind cardiovascular disease, cancer is the second leading cause of death in the majority of developed countries, with foreseen increased incidence in low- and middle-income countries in the upcoming decades [2]. METASTATIC DISSEMINATION Metastatic progression is usually described as a sequence of distinct steps, termed a “metastasis cascade.” These steps include local invasion, intravasation into the circulation (either directly into the bloodstream or via lymphatics and lymph nodes), survival in the circulation, arrest in a new organ, extravasation into the surrounding tissue, and initiation and maintenance of growth at the distant organ site (Figure 1) [6,7,8]. All of these steps must be completed to give rise to a secondary lesion and the success of the process depends on the features of tumor cell, and on local and distant environmental factors, at both cellular and molecular levels [9]. Apoptosis of tumor cells shortly after arriving at the secondary site is considered a major source of failure in the metastatic process [4,10,11]

BIOLOGY OF BRAIN METASTASIS

INITIATION AND MAINTENANCE OF GROWTH AT SECONDARY SITES

Findings

CONCLUSION