Tumor Cell Interactions with the Extracellular Matrix During Invasion and Metastasis

Stetler‐Stevenson, William G.; Aznavoorian, Sadie; Liotta, Lance A.

doi:10.1146/annurev.cb.09.110193.002545

Cited by 1,402 publications

(812 citation statements)

References 113 publications

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“…In vivo, MMP-2 is described as a key enzyme for the degradation of the ECM and facilitating tumour invasion and metastasis, being its active form present in half of all human breast carcinomas (Stetler-Stevenson et al, 1993;Remacle et al, 1998). Not only MMP-2 has pro-invasive activities, but also MMP-1 overexpression has been shown in a variety of advanced carcinomas, being associated with poor prognosis (Murray et al, 1998a, b;Ito et al, 1999;Fujimoto et al, 2008;Okuyama et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Extracellular cleavage and shedding of P-cadherin: a mechanism underlying the invasive behaviour of breast cancer cells

et al. 2009

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Cell-cell adhesion is an elementary process in normal epithelial cellular architecture. Several studies have shown the role mediated by cadherins in this process, besides their role in the maintenance of cell polarity, differentiation and cell growth. However, during tumour progression, these molecules are frequently altered. In breast cancer, tumours that overexpress P-cadherin usually present a high histological grade, show decreased cell polarity and are associated with worse patient survival. However, little is known about how this protein dictates the very aggressive behaviour of these tumours. To achieve this goal, we set up two breast cancer cell models, where P-cadherin expression was differently modulated and analysed in terms of cell invasion, motility and migration. We show that P-cadherin overexpression, in breast cancer cells with wild-type E-cadherin, promotes cell invasion, motility and migration. Moreover, we found that the overexpression of P-cadherin induces the secretion of matrix metalloproteases, specifically MMP-1 and MMP-2, which then lead to P-cadherin ectodomain cleavage. Further, we showed that soluble P-cadherin fragment is able to induce in vitro invasion of breast cancer cells. Overall, our results contribute to elucidate the mechanism underlying the invasive behaviour of P-cadherin expressing breast tumours.

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Section: Discussionmentioning

confidence: 99%

Extracellular cleavage and shedding of P-cadherin: a mechanism underlying the invasive behaviour of breast cancer cells

et al. 2009

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“…This strict tissue organization is lost during the progression of epithelial tumours (carcinomas) and is particularly evident at the invasion stage (Behrens et al, 1992;Stetler-Stevenson et al, 1993). During the invasive process, tumour cells not only lose their cell-cell adhesion properties but also frequently undergo profound changes in their phenotype known as epithelial-mesenchymal transitions (EMTs) (Behrens et al, 1992;Christofori and Semb, 1999), a process reminiscent of EMT occurring at determined stages of development (Nieto, 2002;Thiery, 2002).…”

Section: Introductionmentioning

confidence: 99%

Snail silencing effectively suppresses tumour growth and invasiveness

et al. 2006

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The transcription factor Snail has been recently proposed as an important mediator of tumour invasion because of its role in downregulation of E-cadherin and induction of epithelial-mesenchymal transitions (EMT). This behaviour has led to the consideration of Snail as a potential therapeutic target to block tumour progression. In this report, we provide evidence for this hypothesis. We show that silencing of Snail by stable RNA interference in MDCK-Snail cells induces a complete mesenchymal to epithelial transition (MET), associated to the upregulation of E-cadherin, downregulation of mesenchymal markers and inhibition of invasion. More importantly, stable interference of endogenous Snail in two independent carcinoma cell lines leads to a dramatic reduction of in vivo tumour growth, accompanied by increased tumour differentiation and a significant decrease in the expression of MMP-9 and angiogenic markers and invasiveness. These results indicate that use of RNA interference can be an effective tool for blocking Snail function, opening the way for its application in new antiinvasive therapies.

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“…1 Among the proteases contributing to ECM turnover, the family of matrix metalloproteinases (MMPs) plays a significant role in tumor invasion and metastasis. 2,3 Synthesized as either secreted or membrane-bound latent enzymes, MMPs require proteolytic activation involving cleavage of a propeptide domain to exhibit enzymatic activity.…”

mentioning

confidence: 99%

Upregulation of tissue inhibitor of metalloproteinases (TIMP)-2 promotes matrix metalloproteinase (MMP)-2 activation and cell invasion in a human glioblastoma cell line

Jong

Rajasekaran

et al. 2003

Lab Invest

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Local invasiveness is a characteristic feature of glioblastoma that makes surgical resection nearly impossible and accounts in large part for its poor prognosis. To identify mechanisms underlying glioblastoma invasion and motility, we used Transwell invasion chambers to select for a more potently invasive subpopulation of U87MG human glioblastoma cells. The stable population of tumor cells (U87-C1) obtained through this in vitro selection process were three times more invasive than parental U87MG cells and demonstrated faster monolayer wound healing and enhanced radial motility from cell spheroids. This enhanced invasiveness was associated with an 80% increase in matrix metalloproteinase 2 (MMP-2) activation. No differences in expression levels of pro-MMP-2, membrane-type matrix metalloproteinase I (MT1-MMP), or integrin avb3 (mediators of MMP-2 activation) were detected. However, U87-C1 cells exhibited two-fold elevation of tissue inhibitor of metalloproteinases (TIMP)-2 mRNA and protein relative to parental cells. Exogenous addition of comparable levels of purified TIMP-2 to parental U87MG cells increased MMP-2 activation and invasion. Similarly, U87MG cells engineered to overexpress TIMP-2 at the same levels as U87-C1 cells also demonstrated increased MMP-2 activation, indicating that an increase in physiological levels of TIMP-2 can promote MMP-2 activation and invasion in glioblastoma cells. However, exogenous administration or recombinant overexpression of higher amounts of TIMP-2 in U87MG cells resulted in inhibition of MMP-2 activation. These results demonstrate that the complex balance between TIMP-2 and MMP-2 is a critical determinant of glioblastoma invasion, and indicate that increasing TIMP-2 in glioblastoma patients may potentially cause adverse effects, particularly in tumors containing high levels of MT1-MMP and MMP-2.

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Tumor Cell Interactions with the Extracellular Matrix During Invasion and Metastasis

Cited by 1,402 publications

References 113 publications

Extracellular cleavage and shedding of P-cadherin: a mechanism underlying the invasive behaviour of breast cancer cells

Extracellular cleavage and shedding of P-cadherin: a mechanism underlying the invasive behaviour of breast cancer cells

Snail silencing effectively suppresses tumour growth and invasiveness

Upregulation of tissue inhibitor of metalloproteinases (TIMP)-2 promotes matrix metalloproteinase (MMP)-2 activation and cell invasion in a human glioblastoma cell line

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