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INTRODUCTION and lymphoma and leukemia. [17]

Invasion of tumor cells from primary tumors of the central Patients with CNS metastases present with rather
nervous system (CNS) to organs outside the CNS is a highly unspecific clinical symptoms. Headaches (40-50%), focal
rare event. In contrast, invasion of tumor cells arising neurological deficits (30-40%), and seizures (15-20%) are
outside the CNS to brain, spinal cord, or cerebrospinal fluid the most common presenting symptoms. In leptomeningeal
(CSF) occurs frequently, leading to CNS tumor growth and disease many symptoms are caused by an increased
neoplastic meningitis. Moreover, in approximately every intracranial pressure mainly due to hydrocephalus, which
tenth patient, the diagnosis of brain metastasis is the first leads to nausea and vomiting, neck and back pain, and
sign of the cancer disease. [1] confusion. [3]

CNS metastases are the most common intra-axial MOLECULAR MECHANISMS OF CENTRAL
malignancies, accounting for more than 50% of all brain NERVOUS SYSTEM METASTASIS
tumors, occurring in 20-40% of patients with cancer, and FORMATION AND MAINTENANCE
[2]
leading to symptoms during lifetime in about 60-75%.
[3]
Autopsy series identified CNS metastases in 15-41% Cancers that metastasize to the CNS need to undergo
of patients with known primary cancers at the time of multiple steps, including detachment from the primary site,
death. [4-8] Most metastatic manifestations affect the brain invasion, intravasation into the bloodstream, extravasation,
parenchyma; 80% are found supratentorially and 20% survival, and proliferation. Even with different primary
infratentorially (15% cerebellum, 5% in the brain stem), tumor origins, invasion and proliferation into the CNS
with the spinal cord most infrequently involved. The appears to be associated with similar molecular programs
incidence of single vs. multiple sites of CNS metastasis and is highly supported and maintained by the tumor-
is approximately equal. In about 4-15% of patients with associated brain microenvironment. [18]
[9]
CNS disease, CSF is involved. Lung cancer, breast
[10]
cancer, and melanoma are the primary malignancies that First, the growth of metastatic brain tumors is critically
[19]
contribute to 80% of brain metastases. [7,11,12] Moreover, dependent on angiogenesis, so therapies targeting
there is a high incidence of asymptomatic CNS metastases, this process might be important in the prevention or
so it is hard to estimate their true prevalence. Current management of brain metastases. In a mouse model of
studies estimate that approximately a third of patients with brain metastases [HER2-amplified breast cancer cells
cancer eventually develop brain metastases. [10] in an orthotopic xenografting of human BT-474 cells],
extracranial disease was successfully controlled using
Several reasons may explain the increase in incidence the HER2 inhibitors trastuzumab or lapatinib, but tumor
of brain metastases over the past decades: Certainly, control with monotherapy in the brain failed. By adding
the widespread use and improvements in new imaging anti-VEGFR2 antibodies, however, tumor growth in the
technologies facilitates the detection of metastatic lesions. brain was better controlled, leading to improved survival,
For example, magnetic resonance imaging (MRI) of especially with a combination of lapatinib, trastuzumab,
the neuraxis is currently used for the examination of and anti-VEGFR2 antibody treatment. [20]
approximately 60-70% of patients with cancer; 20 years
ago, it was used in 2% of cancer patients. The global Second, astrocytes are intimately involved in maintaining
[13]
increase in cancer prevalence is another contributing factor, normal homeostasis of the brain microenvironment,
especially the increase in cancers that have a tendency accomplished through transport of nutrients to the neurons
to invade the CNS, such as lung cancer. Moreover, the and facilitation of neural signal transduction. In fact,
introduction of targeted therapies that have limited activated astrocytes induced upregulation of survival
bioavailability in the CNS might also have resulted in an genes. These mechanisms usually protect injured neurons
increase of CNS metastases (e.g. the treatment of human from apoptosis, but can be abused by tumor cells (e.g. for
epidermal growth factor receptor protein 2(HER2)-positive protection from cytotoxic effects of chemotherapeutic
breast cancer with trastuzumab, a compound with limited agents). [21,22] A very interesting study on the impact of
penetration from the blood to the CSF). [14,15] astrocyte-derived reshaping of the brain microenvironment
was recently published by Zhang and colleagues: Mouse
Neoplastic meningitis (also referred to as meningeosis tumor cells lost PTEN expression only after dissemination
neoplastica or, based on the underlying tumor, as to the brain, but not to other organs, and PTEN levels
meningeosis carinomatosa, gliomatosa, or lymphomatosa) in PTEN-loss brain metastatic tumor cells were again
is a spread of tumor cells into the subarachnoid space. rescued after leaving the brain microenvironment. This
It is found in approximately 5-10% of all patients with brain microenvironment-dependent plasticity of PTEN
malignant tumors and is a condition frequently diagnosed expression is epigenetically regulated by astrocyte-derived
in late stage cancer. The most common associated exosomes mediating an intercellular transfer of PTEN-
[16]
primary tumors are lung cancer, breast cancer, melanoma targeting microRNAs to metastatic tumor cells. As a

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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ May 20, 2016 ¦