The Vascular Basement Membrane as “Soil” in Brain Metastasis

Carbonell, W. Shawn; Ansorge, Olaf; Sibson, Nicola R.; Muschel, Ruth J.

doi:10.1371/journal.pone.0005857

Cited by 285 publications

(293 citation statements)

References 48 publications

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“…The integrin receptor is a heterodimeric complex made of a-and b-subunits (16). The b1-integrin subunit has been implicated in the control of invasion and migration, and therefore metastasis (17,18). Integrin-linked kinase (ILK) forms a signaling hub at the b-integrin tail, signaling downstream through parvin proteins, PINCH, and NCK-2 (19,20).…”

Section: Introductionmentioning

confidence: 99%

Targeting Cell Spreading: A Method of Sensitizing Metastatic Tumor Cells to TRAIL-Induced Apoptosis

Phipps

Hino

Muschel

2011

Molecular Cancer Research

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TNF-related apoptosis-inducing ligand (TRAIL) is a current focus for the development of new cancer therapies, because of its selective induction of apoptosis in cancer cells. TRAIL has previously been shown to be important for tumor cell clearance from the liver; however, many cancer cell lines show some resistance toward TRAIL, posing a problem for the future use of TRAIL therapies. In this study, we show that interfering with a cell's ability to attach and spread onto a matrix can sensitize tumor cells to TRAIL-induced apoptosis in vitro. We targeted different members of the integrin signaling pathway using siRNA or inhibitors, including b-integrins, talin, Src, and downstream survival pathways PI3K and MAPK. Targeting any of these molecules could sensitize both MDA-MB-231 human breast cancer cells and TRAIL-resistant 1205Lu melanoma cells to TRAIL-induced apoptosis in vitro. Transcriptionally targeting the cytoskeleton, using myocardin-related transcription factor depletion to disrupt the transcription of cytoskeletal proteins, also caused TRAIL sensitization in MDA-MB-231 cells. We showed that this sensitivity to TRAIL correlated with increased activation of the intrinsic pathway of apoptosis. Manipulation of cell spreading therefore presents a potential method by which disseminated tumor cells could be sensitized to TRAIL therapies in vivo. Mol Cancer Res; 9(3); 249-58. Ó2011 AACR.

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Section: Introductionmentioning

confidence: 99%

Targeting Cell Spreading: A Method of Sensitizing Metastatic Tumor Cells to TRAIL-Induced Apoptosis

Phipps

Hino

Muschel

2011

Molecular Cancer Research

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“…In particular, vascular cell adhesion molecule-1 (VCAM-1) has been shown to play an important role in leukocyte recruitment to the brain in neurological disease both in animal models and humans (7)(8)(9)(10). We and others have previously shown a close association of tumor colonies with the existing cerebral vasculature both in murine models of brain metastasis and human postmortem brain tissue containing metastases (11,12). These findings suggest that activation of the vascular endothelium is likely to occur during metastasis development.…”

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confidence: 99%

Molecular MRI enables early and sensitive detection of brain metastases

Serres

Soto

Hamilton

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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129

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Metastasis to the brain is a leading cause of cancer mortality. The current diagnostic method of gadolinium-enhanced MRI is sensitive only to larger tumors, when therapeutic options are limited. Earlier detection of brain metastases is critical for improved treatment. We have developed a targeted MRI contrast agent based on microparticles of iron oxide that enables imaging of endothelial vascular cell adhesion molecule-1 (VCAM-1). Our objectives here were to determine whether VCAM-1 is up-regulated on vessels associated with brain metastases, and if so, whether VCAM-1-targeted MRI enables early detection of these tumors. Early up-regulation of cerebrovascular VCAM-1 expression was evident on tumor-associated vessels in two separate murine models of brain metastasis. Metastases were detectable in vivo using VCAM-1-targeted MRI 5 d after induction (<1,000 cells). At clinical imaging resolutions, this finding is likely to translate to detection at tumor volumes two to three orders of magnitude smaller (0.3-3 × 10 5 cells) than those volumes detectable clinically (10 7 -10 8 cells). VCAM-1 expression detected by MRI increased significantly (P < 0.0001) with tumor progression, and tumors showed no gadolinium enhancement. Importantly, expression of VCAM-1 was shown in human brain tissue containing both established metastases and micrometastases. Translation of this approach to the clinic could increase therapeutic options and change clinical management in a substantial number of cancer patients.

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“…Brain metastases are the most common malignant tumor of the CNS outnumbering primary brain tumors such as glioma and glioblastoma (17). Although the major requirements for metastasis to distant sites remain incompletely understood, clinically, brain metastases most commonly arise from lung, breast and skin cancers (18,19).…”

Section: Discussionmentioning

confidence: 99%

Antitumor effects of genetically engineered stem cells expressing yeast cytosine deaminase in lung cancer brain metastases via their tumor-tropic properties

Kim

et al. 2012

Oncol Rep

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Abstract. Although mortality related with primary tumors is approximately 10%, metastasis leads to 90% of cancerassociated death. The majority of brain metastases result from lung cancer, but the metastatic mechanism remains unclear. In general, chemotherapy for treating brain diseases is disrupted by the brain blood barrier (BBB). As an approach to improve treatment of lung cancer metastasis to the brain, we employed genetically engineered stem cells (GESTECs), consisting of neural stem cells (NSCs) expressing a suicide gene. Cytosine deaminase (CD), one of the suicide genes, originating from bacterial (bCD) or yeast (yCD), which can convert the nontoxic prodrug, 5-fluorocytosine (5-FC), into 5-fluorouracil (5-FU), can inhibit cancer cell growth. We examined the therapeutic efficacy and migratory properties of GESTECs expressing yCD, designated as HB1.F3.yCD, in a xenograft mouse model of lung cancer metastasis to the brain. In this model, A549 lung cancer cells were implanted in the right hemisphere of the mouse brain, while CM-DiI pre-stained HB1.F3.yCD cells were implanted in the contralateral brain. Two days after the injection of stem cells, 5-FC was administered via intraperitoneal injection. The tumor-tropic effect of HB1.F3.yCD was evident by fluorescent analysis, in which red-colored stem cells migrated to the lung tumor mass of the contralateral brain. By histological analysis of extracted brain, the therapeutic efficacy of HB1.F3.yCD in the presence of 5-FC was confirmed by the reduction in density and aggressive tendency of lung cancer cells following treatment with 5-FC, compared to a negative control or HB1.F3.yCD injection without 5-FC. Taken together, these results indicate that HB1. F3.yCD expressing a suicide gene may be a new therapeutic strategy for lung cancer metastases to the brain in the presence of a prodrug. IntroductionMetastasis is an insidious movement of cancer cells from primary tumor sites to distant organs and tissues, including the brain, liver, and bones, via blood and lymphatic vessels. Metastasis accounts for over 90% of lethality in cancer patients (1). Particularly, brain metastasis is the most common intracranial neoplasm and arises in 10-40% of all cancer patients (2). Because metastases in the brain may rapidly compromise central nervous system (CNS) function, it is a significant cause of cancer-related morbidity and mortality worldwide (3). The most common origins of brain metastases include primary cancers of the lung, breast and skin (4). Lung cancer, the most prevalent cancer in men, is the leading cause of cancer-related death in the developed world (5). Of all malignancies, primary lung cancer has the highest incidence for brain metastasis and approximately 40% of all patients with lung cancer develop brain metastasis, followed by breast cancer (6). For treating these brain metastases, therapies usually include surgery, chemotherapy, and radiotherapy, but these therapies have many side effects in the nervous system (7). Therefore, brain metastasis is a very critic...

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The Vascular Basement Membrane as “Soil” in Brain Metastasis

Cited by 285 publications

References 48 publications

Targeting Cell Spreading: A Method of Sensitizing Metastatic Tumor Cells to TRAIL-Induced Apoptosis

Targeting Cell Spreading: A Method of Sensitizing Metastatic Tumor Cells to TRAIL-Induced Apoptosis

Molecular MRI enables early and sensitive detection of brain metastases

Antitumor effects of genetically engineered stem cells expressing yeast cytosine deaminase in lung cancer brain metastases via their tumor-tropic properties

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