Brain metastases are among the most feared complications in breast cancer, as no therapy exists that prevents or eliminates breast cancer spreading to the brain. New therapeutic strategies depend on specific knowledge of tumor cell properties that allow breast cancer cell growth within the brain tissue. To provide information in this direction, we established a human breast cancer cell model for brain metastasis based on circulating tumor cells from a breast cancer patient and variants of these cells derived from bone or brain lesions in immunodeficient mice. The brain-derived cells showed an increased potential for brain metastasis in vivo and exhibited a unique protein expression profile identified by large-scale proteomic analysis. This protein profile is consistent with either a selection of predisposed cells or bioenergetic adaptation of the tumor cells to the unique energy metabolism of the brain. Increased expression of enzymes involved in glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation pathways suggests that the brain metastatic cells derive energy from glucose oxidation. The cells further showed enhanced activation of the pentose phosphate pathway and the glutathione system, which can minimize production of reactive oxygen species resulting from an enhanced oxidative metabolism. These changes promoted resistance of brain metastatic cells to drugs that affect the cellular redox balance. Importantly, the metabolic alterations are associated with strongly enhanced tumor cell survival and proliferation in the brain microenvironment. Thus, our data support the hypothesis that predisposition or adaptation of the tumor cell energy metabolism is a key element in breast cancer brain metastasis, and raise the possibility of targeting the functional differentiation in breast cancer brain lesions as a novel therapeutic strategy. [Cancer Res 2007;67(4):1472-86]
- Awareness of the gold standard paradox is necessary when using traditional pathologist scores to analytically validate a tIA tool because image analysis is used specifically to overcome known sources of bias in visual assessment of tissue sections.
We have shown that ER-negative and invasive human breast cancer cell lines MDA-MB-468 and MDA-MB-231 have constitutively higher mitogen activated protein kinase (ERK1&2/MAPK) when compared to the ERpositive and non-invasive MCF-7 human breast cancer cells. In MCF-7 cells, TGFa stimulation induced only transient MAPK activation, leading to a transient increase in cell migration. However, MDA 231 and MDA 468 cells, TGFa stimulation induced sustained MAPK activation, which correlated with enhanced cell motility and in vitro invasion. Serum stimulation activates ERK/MAPK activity persistently in both ER-positive and ER-negative breast cancer cells, leading to enhanced and sustained cell migration. Inhibition of MAPK activation by anti-sense MEK expression in MDA-MB-468 cells signi®cantly inhibits cell migration and in vitro invasion. In contrast, MCF-7 cells expressing constitutively activated MEK show a signi®cant increase in MAPK activity and cell migration, but this failed to enhance in vitro invasion. The kinetic pro®les of MAPK activation and inhibition show a relationship between the duration and magnitude of MAPK activation and cell migration in both ER-positive and ER-negative human breast cancer cells. These studies show that cell motility is modulated by the magnitude and the duration of MAPK activation; but increased activation of MAPK may not be su cient to allow in vitro invasion in noninvasive MCF-7 breast cancer cells. Oncogene (2001) 20, 4209 ± 4218.
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...
Quantitative clinical measurement of heterogeneity in immunohistochemistry staining would be useful in evaluating patient therapeutic response and in identifying underlying issues in histopathology laboratory quality control. A heterogeneity scoring approach (HetMap) was designed to visualize a individual patient's immunohistochemistry heterogeneity in the context of a patient population. HER2 semiquantitative analysis was combined with ecology diversity statistics to evaluate cell-level heterogeneity (consistency of protein expression within neighboring cells in a tumor nest) and tumor-level heterogeneity (differences of protein expression across a tumor as represented by a tissue section). This approach was evaluated on HER2 immunohistochemistry-stained breast cancer samples using 200 specimens across two different laboratories with three pathologists per laboratory, each outlining regions of tumor for scoring by automatic cell-based image analysis. HetMap was evaluated using three different scoring schemes: HER2 scoring according to American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP) guidelines, H-score, and a new continuous HER2 score (HER2 cont ). Two definitions of heterogeneity, cell-level and tumor-level, provided useful independent measures of heterogeneity. Cases where pathologists had disagreement over reads in the area of clinical importance ( þ 1 and þ 2) had statistically significantly higher levels of tumor-level heterogeneity. Cell-level heterogeneity, reported either as an average or the maximum area of heterogeneity across a slide, had low levels of dependency on the pathologist choice of region, while tumor-level heterogeneity measurements had more dependence on the pathologist choice of regions. HetMap is a measure of heterogeneity, by which pathologists, oncologists, and drug development organizations can view cell-level and tumor-level heterogeneity for a patient for a given marker in the context of an entire patient cohort. Heterogeneity analysis can be used to identify tumors with differing degrees of heterogeneity, or to highlight slides that should be rechecked for QC issues. Tumor heterogeneity plays a significant role in disconcordant reads between pathologists.
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