Urokinase Plasminogen Activator and Urokinase Plasminogen Activator Receptor Mediate Human Stem Cell Tropism to Malignant Solid Tumors

Gutova, Margarita; Najbauer, Joseph; Frank, R.T.; Kendall, Stephen E.; Gevorgyan, Anna; Metz, Marianne Z.; Guevorkian, Mark; Edmiston, Marissa; Zhao, Donghong; Glackin, Carlotta A.; Kim, Seung Up; Aboody, Karen S.

doi:10.1634/stemcells.2008-0141

Cited by 105 publications

(65 citation statements)

References 38 publications

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“…The direct link between uPA and cancer stem cells (CSCs) or MDR proteins has not been reported. Gutova et al (2008) have recently shown that uPA can mediate human stem cell tropism to malignant solid tumours by chemotaxis and cell guidance. Here, we first showed the colocalisation of uPA and CD44 in primary and metastatic EOC cells, and the direct link between uPA and MDR proteins (MDR1 and MRP2).…”

Section: Discussionmentioning

confidence: 99%

Coexpression of invasive markers (uPA, CD44) and multiple drug-resistance proteins (MDR1, MRP2) is correlated with epithelial ovarian cancer progression

et al. 2009

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BACKGROUND: Invasion and metastases of cancer cells and the development of resistance to anticancer therapies are the main causes of treatment failure and mortality in cancer patients. METHODS: We evaluated invasive markers of urokinase plasminogen activator (uPA) and CD44 and multiple drug-resistance (MDR) markers of MDR1 and MRP2 in four epithelial ovarian cancer (EOC) cell lines, primary tumours (n ¼ 120) and matched metastatic lesions (n ¼ 40) by immunofluoresence labelling. We correlated uPA and CD44 with MDR markers in primary and metastatic cells using confocal microscope. We also investigated the relationship of the expression of uPA, CD44 and MDR1 with various progression parameters. RESULTS: The coexpression of uPA and CD44 with MDR markers was found in primary and metastatic cells. The overexpression of uPA, CD44 and MDR1 was found in most primary and matched metastatic lesions of EOC, and was significantly associated with tumour stage, grade, residual disease status, relapse and presence of ascites (Po0.05), but not with histology type (P40.05). CONCLUSIONS: Our results suggest that the overexpression of uPA, CD44 and MRD1 is correlated with EOC progression; both uPA and CD44 are related with drug resistance during EOC metastasis and could be useful therapeutically.

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Section: Discussionmentioning

confidence: 99%

Coexpression of invasive markers (uPA, CD44) and multiple drug-resistance proteins (MDR1, MRP2) is correlated with epithelial ovarian cancer progression

et al. 2009

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“…Early on, due to the high affinity of HSCs and their leukocyte progeny for wound and tumor sites, investigators looked to the already wellcharacterized processes of HSC and leukocyte homing for clues driving MSC migration. 96,97 Indeed, factors involved in HSC and immunocyte recruitment, such as monocyte chemotactic protein-1 (MCP-1), 98 stromal-cell derived factor (SDF-1), 99 cyclophilin B and hepatoma-derived growth factor (HDGF), 100 urokinase plasminogen activator (uPA), 101,102 interleukin (IL-)6, 103 basic fibroblast growth factor (bFGF) 104 and vascular endothelial growth factor (VEGF) 104 have all been implicated in driving the tropism of bone-marrow-derived MSCs to tumors. It is believed that an active inflammatory response is necessary to allow MSC recruitment to tumor sites.…”

Section: Msc Homing To Tumorsmentioning

confidence: 99%

Mesenchymal stem cells in tumor development

Cuiffo¹,

Karnoub²

2012

Cell Adhesion & Migration

186

120

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“…(28). Secreted ligands may be recognized by HB1.F3.yCD cells, and a tumor specific migratory property may be stimulated by these stem cells (29).…”

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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Urokinase Plasminogen Activator and Urokinase Plasminogen Activator Receptor Mediate Human Stem Cell Tropism to Malignant Solid Tumors

Abstract: ABSTRACT

Cited by 105 publications

References 38 publications

Coexpression of invasive markers (uPA, CD44) and multiple drug-resistance proteins (MDR1, MRP2) is correlated with epithelial ovarian cancer progression

Coexpression of invasive markers (uPA, CD44) and multiple drug-resistance proteins (MDR1, MRP2) is correlated with epithelial ovarian cancer progression

Mesenchymal stem cells in tumor development

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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