Brain metastases are diagnosed in 10 to 40% of all cancer patients, and the incidence is rising as patients live longer due to improved treatments for extracranial metastases.1,2 Brain lesions are most frequently associated with lung cancer, breast cancer, and melanoma. 1,2 Unfortunately, brain metastases are still very difficult to treat and the mechanisms underlying their establishment and progression are poorly understood. Thus, information in this direction and models for analysis are a prerequisite for the development of new, efficient therapies.The essential role of the tumor microenvironment in cancer progression has been well documented for extracranial malignancies, and recent findings indicate that the tumor microenvironment might be a suitable target in anticancer therapies, as well as a valuable biomarker for prognostic purposes.3-5 The brain provides a unique environment with paracrine growth factors that differ from most other organs. 6,7 The involvement of brain-resident cells including brain endothelial cells, microglia, and astrocytes in the pathology of primary and metastatic brain tumors is only partially understood. Brain endothelial cells are the first host cell type that circulating cancer cells encounter when they arrest within the brain microvasculature. In addition to posing the initial barrier for brain invasion, endothelial cells and their basement membrane seem to play important roles in supporting the growth of brain metastases as well as brain tumor stem cells. 8 -10
Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer associated with a very poor prognosis. Recently, the initiation and growth of GBM has been linked to brain tumor-initiating cells (BTICs), which are poorly differentiated and share features with neural stem cells (NSCs). Here we describe a kinome-wide RNA interference screen to identify factors that control the tumorigenicity of BTICs. We identified several genes whose silencing induces differentiation of BTICs derived from multiple GBM patients. In particular, knockdown of the adaptor protein TRRAP significantly increased differentiation of cultured BTICs, sensitized the cells to apoptotic stimuli, and negatively affected cell cycle progression. TRRAP knockdown also significantly suppressed tumor formation upon intracranial BTIC implantation into mice. Together, these findings support a critical role for TRRAP in maintaining a tumorigenic, stem cell-like state.
The incidence of brain metastasis is rising and poses a severe clinical problem, as we lack effective therapies and knowledge of mechanisms that control metastatic growth in the brain. Here we demonstrate a crucial role for high-affinity tumor cell integrin ␣v3 in brain metastatic growth and recruitment of blood vessels. Although ␣v3 is frequently up-regulated in primary brain tumors and metastatic lesions of brain homing cancers, we show that it is the ␣v3 activation state that is critical for brain lesion growth. Activated, but not non-activated, tumor cell ␣v3 supports efficient brain metastatic growth through continuous up-regulation of vascular endothelial growth factor (VEGF) protein under normoxic conditions. In metastatic brain lesions carrying activated ␣v3, VEGF expression is controlled at the post-transcriptional level and involves phosphorylation and inhibition of translational respressor 4E-binding protein (4E-BP1). In contrast, tumor cells with nonactivated ␣v3 depend on hypoxia for VEGF induction, resulting in reduced angiogenesis, tumor cell apoptosis, and inefficient intracranial growth. Importantly, the microenvironment critically influences the effects that activated tumor cell ␣v3 exerts on tumor cell growth. Although it strongly promoted intracranial growth, the activation state of the receptor did not influence tumor growth in the mammary fat pad as a primary site. Thus, we identified a mechanism by which metastatic cells thrive in the brain microenvironment and use the high-affinity form of an adhesion receptor to grow and secure host support for proliferation. Targeting this molecular mechanism could prove valuable for the inhibition of brain metastasis.angiogenesis ͉ brain metastasis ͉ integrin activation ͉ 4E-BP1 B rain metastases are diagnosed in 10% to 40% of patients with progressing cancer, and the incidence is rising as patients live longer and extracranial metastases respond to improved treatments. However, brain metastases still cannot be treated effectively, and mechanisms controlling brain metastatic growth are largely unknown (1-3).Here, we demonstrate that the high-affinity state of tumor cell adhesion receptor integrin ␣ v  3 critically promotes metastatic growth and recruitment of supporting blood vessels within the brain microenvironment. Integrins are cell surface receptors composed of non-covalently linked ␣ and  subunits that mediate cell-matrix and cell-cell interactions and transduce signals that have impacts on cell survival, proliferation, adhesion, migration, and invasion. Integrin signals can also originate inside cells, affect receptor affinity, and thereby control ligand binding, cross talk with other receptors, and alter cell adhesion and proliferation (4-6). Integrin ␣ v  3 also plays a role on sprouting endothelial cells and contributes to angiogenesis (7). In several tumor types, including glioma, breast cancer, and melanoma, expression of ␣ v  3 supports invasion and metastasis (8-11). Notably, these tumors either originate in the brain or freque...
In addition to malignant cancer cells, tumors contain a variety of different stromal cells that constitute the tumor microenvironment. Some of these cell types provide crucial support for tumor growth, while others have been suggested to actually inhibit tumor progression. The composition of tumor microenvironment varies depending on the tumor site. The brain in particular consists of numerous specialized cell types such as microglia, astrocytes, and brain endothelial cells. In addition to these brain-resident cells, primary and metastatic brain tumors have also been shown to be infiltrated by different populations of bone marrow-derived cells. The role of different cell types that constitute tumor microenvironment in the progression of brain malignancies is only poorly understood. Tumor microenvironment has been shown to be a promising therapeutic target and diagnostic marker in extracranial malignancies. A better understanding of tumor microenvironment in the brain would therefore be expected to contribute to the development of improved therapies for brain tumors that are urgently required due to a poor availability of treatments for these malignancies. This review summarizes some of the known interactions between brain tumors and different stromal cells, and also discusses potential therapeutic approaches within this context.
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