Pathobiology of Brain Metastases: Molecular Mechanisms

Introduction

Metastatic brain tumors (MBT) arise from cancers outside the central nervous system (CNS). They reach the brain either from hematogenous spread or via direct invasion from adjacent tissues. Brain metastases are the most common brain tumors and occur nearly 200,000 times each year in the USA. They comprise about 25% of all cancer metastases and may be seen in about 20–40% of all adult cancer patients. The number of cases for the site of origin is 40–50% for lung, 15–20% for breast, 5–10% for skin, and 4–6% for the gastrointestinal tract ( ). Brain metastases are the leading cause of morbidity and mortality in cancer patients. Median survival time for untreated patients is 5 weeks; multimodality therapy may extend survival to 3–18 months ( ). Recently, an increased incidence of MBTs has been noted likely secondary to improved imaging modalities and possibly more effective systemic treatment of primary tumors ( ).

The vast majority of MBTs occur in the cerebral hemispheres (80%) with a much smaller number appearing in the cerebellum (15%) and the brainstem (5%). These percentages roughly correspond to the relative tissue volumes of the respective portions of the brain. MBTs tend to distribute along gray-white junctions and watershed vascular distributions where the circulating tumor cells lodge in capillary beds prior to growing into symptomatic lesions ( ). MBTs are a major cause of morbidity and mortality in patients with metastatic cancer. The clinical symptoms of MBTs may be nonspecific such as headaches from raised intracranial pressure, cognitive impairment, or more specifically correlated to location and present with seizure or focal neurological deficits ( ).

The brain, enclosed by the meninges, has a unique perivascular environment thanks to the blood–brain-barrier (BBB), a selectively permeable tissue found around most blood vessels that limits the movement of molecules from the blood, based upon molecular size and charge. The BBB prevents the entry of most hydrophilic chemotherapeutics, thereby acting as a refuge for metastatic tumors ( ). Furthermore, the BBB acts as an immune refuge, limiting exposure of the brain parenchymal tissues to circulating antigens.

In addition, the BBB provides a microenvironment that is tightly metabolically regulated for the metastatic cells that have arrested in brain vasculature, extravasated, and begun to proliferate either in the perivascular space or the brain parenchyma. The brain’s interstitial fluid has high chloride content enabling clones of neuroepithelial origin, such as small cell carcinoma of the lung or melanoma, to proliferate while sometimes inhibiting the growth of other cancer cell types lacking this predilection ( ).

This chapter will focus on MBT, the hallmarks of the metastatic cascade, the genetics, and pathobiology of brain metastases. By understanding the molecular events that sustain brain metastases, a foundation may be created to allow the investigation and development of more effective targeted therapies and research directions.

Pathobiology of Brain Metastasis

Metastases develop when tumor cells manage to evade the homeostatic mechanisms within the host to exploit the cytoprotective features provided by the brain’s microenvironment. The “seed-and-soil” hypothesis of metastasis states that the metastatic “seed” from the primary tumor can only grow in appropriate fertile “soil” of the host organ. This implies that the successful outgrowth of deadly metastatic tumors depends on the bidirectional interaction between the metastatic cancer cells and host tissue site-specific microenvironment ( ). To form a metastasis, a tumor cell must complete a sequential series of steps that begins with its detachment from the primary mass and invasion of the surrounding tissue. The cascade involves two distinct stages: (1) migration which includes intravasation, dissemination, and extravasation; (2) colonization and metastatic proliferation.