Matrix metalloproteinase-1 expression enhances tumorigenicity as well as tumor-related angiogenesis and is inversely associated with TIMP-4 expression in a model of glioblastoma

Pullen, Nick; Anand, Monika; Cooper, Patricia S.; Fillmore, Helen L.

doi:10.1007/s11060-011-0691-5

Cited by 30 publications

(23 citation statements)

References 42 publications

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“…The latter phenotype may be considered as the most clinically-relevant model displaying all the typical features of glioblastoma, while the other two enable a separate interrogation of the angiogenic and/or invasive component of glioblastoma in patient-derived pre-clinical models. We found that angiogenesis was associated with increased tumour malignancy and decreased mouse survival, in line with clinical data (progression from low to high grade gliomas) and with numerous experimental studies [18-20]. The more pronounced neurological symptoms are likely due to the presence of oedema and strong intracranial pressure.…”

Section: Discussionsupporting

confidence: 87%

Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma

et al. 2016

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The histopathological and molecular heterogeneity of glioblastomas represents a major obstacle for effective therapies. Glioblastomas do not develop autonomously, but evolve in a unique environment that adapts to the growing tumour mass and contributes to the malignancy of these neoplasms. Here, we show that patient-derived glioblastoma xenografts generated in the mouse brain from organotypic spheroids reproducibly give rise to three different histological phenotypes: (i) a highly invasive phenotype with an apparent normal brain vasculature, (ii) a highly angiogenic phenotype displaying microvascular proliferation and necrosis and (iii) an intermediate phenotype combining features of invasion and vessel abnormalities. These phenotypic differences were visible during early phases of tumour development suggesting an early instructive role of tumour cells on the brain parenchyma. Conversely, we found that tumour-instructed stromal cells differentially influenced tumour cell proliferation and migration in vitro, indicating a reciprocal crosstalk between neoplastic and non-neoplastic cells. We did not detect any transdifferentiation of tumour cells into endothelial cells. Cell type-specific transcriptomic analysis of tumour and endothelial cells revealed a strong phenotype-specific molecular conversion between the two cell types, suggesting co-evolution of tumour and endothelial cells. Integrative bioinformatic analysis confirmed the reciprocal crosstalk between tumour and microenvironment and suggested a key role for TGFβ1 and extracellular matrix proteins as major interaction modules that shape glioblastoma progression. These data provide novel insight into tumour-host interactions and identify novel stroma-specific targets that may play a role in combinatorial treatment strategies against glioblastoma.

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Section: Discussionsupporting

confidence: 87%

Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma

et al. 2016

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“…Because these secreted MMPs cleave the extracellular matrix, they are essential factors for invasion [31], [34]. MMPs have been shown to contribute to tumorigenicity; the over-expression of MMP1 enhances tumorigenicity, while its knockdown reduces tumor formation in a glioblastoma cell line [35]. In non-small cell lung cancers, MMP10 plays a pertinent role in tumor initiation, and it maintains the characteristics of CSCs [36].…”

Section: Discussionmentioning

confidence: 99%

CD271 Defines a Stem Cell-Like Population in Hypopharyngeal Cancer

et al. 2013

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Cancer stem cells contribute to the malignant phenotypes of a variety of cancers, but markers to identify human hypopharyngeal cancer (HPC) stem cells remain poorly understood. Here, we report that the CD271+ population sorted from xenotransplanted HPCs possesses an enhanced tumor-initiating capability in immunodeficient mice. Tumors generated from the CD271+ cells contained both CD271+ and CD271− cells, indicating that the population could undergo differentiation. Immunohistological analyses of the tumors revealed that the CD271+ cells localized to a perivascular niche near CD34+ vasculature, to invasive fronts, and to the basal layer. In accordance with these characteristics, a stemness marker, Nanog, and matrix metalloproteinases (MMPs), which are implicated in cancer invasion, were significantly up-regulated in the CD271+ compared to the CD271− cell population. Furthermore, using primary HPC specimens, we demonstrated that high CD271 expression was correlated with a poor prognosis for patients. Taken together, our findings indicate that CD271 is a novel marker for HPC stem-like cells and for HPC prognosis.

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“…Additionally, expression of collagenases, such as MMP-1 and MMP-13, is deregulated in various cancers (9). MMP-1 expression has been documented to occur in GBM cells (4,21), and increased expression correlates with increased tumor grade (58,71) and tumorigenicity (52), and decreased survival in GBM patients (71). Moreover, increased MMP-13 production in glioma cells in response to various stimuli leads to an increase in migration and invasion (43).…”

Section: Discussionmentioning

confidence: 99%

EphrinA1 Is Released in Three Forms from Cancer Cells by Matrix Metalloproteases

Beauchamp

Lively

Mintz

et al. 2012

Molecular and Cellular Biology

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EphrinA1 is a glycosylphosphatidylinositol (GPI)-linked ligand for the EphA2 receptor, which is overexpressed in glioblastoma (GBM), among other cancers. Activation of the receptor by ephrinA1 leads to a suppression of oncogenic properties of GBM cells. We documented that a monomeric functional form of ephrinA1 is released from cancer cells and thus explored the mechanism of ephrinA1 release and the primary protein sequence. We demonstrate here that multiple metalloproteases (MMPs) are able to cleave ephrinA1, most notably MMP-1, -2, -9, and -13. The proteolytic cleavage that releases ephrinA1 occurs at three positions near the C terminus, producing three forms ending in valine-175, histidine-177, or serine-178. Moreover, deletion of amino acids 174 to 181 or 175 to 181 yields ephrinA1 that is still GPI linked but not released by proteolysis, underlining the necessity of amino acids 175 to 181 for release from the membrane. Furthermore, recombinant ephrinA1 ending at residue 175 retains activity toward the EphA2 receptor. These findings suggest a mechanism of release and provide evidence for the existence of several forms of monomeric ephrinA1. Moreover, ephrinA1 should be truncated at a minimum at amino acid 175 in fusions or conjugates with other molecules in order to prevent likely proteolysis within physiological and pathobiological environments.

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Matrix metalloproteinase-1 expression enhances tumorigenicity as well as tumor-related angiogenesis and is inversely associated with TIMP-4 expression in a model of glioblastoma

Cited by 30 publications

References 42 publications

Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma

Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma

CD271 Defines a Stem Cell-Like Population in Hypopharyngeal Cancer

EphrinA1 Is Released in Three Forms from Cancer Cells by Matrix Metalloproteases

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