Tissue plasminogen activator is required for the growth, invasion, and angiogenesis of pancreatic tumor cells

Dı́az, Vı́ctor M.; Planagumà, Jesús; Thomson, Timothy M.; Reventós, Jaume; Paciucci, Rosanna

doi:10.1053/gast.2002.31885

Cited by 63 publications

(61 citation statements)

References 48 publications

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“…Some of them are more related to angiogenesis in the context of tumour progression and invasion, such as PLAT (tissue plasminogen activator; cluster 1), TIMP2, MMP2 and MET (hepatocyte growth factor receptor; cluster 2; Fridman et al 1992, Diaz et al 2002, Ma et al 2003. Genes with higher mRNA levels during the luteal phase, which are more directly involved in angiogenesis are ephrin-A1 (EFNA1), endothelial differentiation sphingolipid G-protein-coupled receptor, 3 (EDG3), angiotensinogen (AGT), endothelial PAS domain protein 1 (EPAS1; hypoxia-inducible factor 2-a) and Kruppel-like factor 5 (KLF5; clusters 1, 1, 2, 1, 2).…”

Section: Discussionmentioning

confidence: 99%

Dynamic changes in messenger RNA profiles of bovine endometrium during the oestrous cycle

Mitko¹,

Ulbrich²,

Wenigerkind³

et al. 2008

Reproduction

115

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During the oestrous cycle, the bovine endometrium exhibits characteristic morphological and functional changes, which are mainly induced by progesterone (P 4 ), oestrogens and oxytocin. We studied the response of the endometrium to this changing hormonal environment at the transcriptome level using a custom-made cDNA microarray. Endometrium samples were recovered from Simmental heifers on days 0 (oestrus), 3.5 (metoestrus), 12 (dioestrus) and 18. The latter group was divided into animals with high (late dioestrus) and low P 4 levels (preoestrus). Significance analysis of microarrays revealed 269 genes exhibiting significant changes in their transcript levels during the oestrous cycle in distinct temporal patterns. Two major types of expression profiles were observed, which showed the highest mRNA levels during the oestrus phase or the highest levels during the luteal phase respectively. A minor group of genes exhibited the highest mRNA levels on day 3.5. Gene ontology (GO) analyses revealed GO categories related to extracellular matrix remodelling, transport, and cell growth and morphogenesis enriched at oestrus, whereas immune response and particular metabolic pathways were overrepresented at dioestrus.

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Section: Discussionmentioning

confidence: 99%

Dynamic changes in messenger RNA profiles of bovine endometrium during the oestrous cycle

Mitko¹,

Ulbrich²,

Wenigerkind³

et al. 2008

Reproduction

115

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“…39 -41 The pleiotropic effects of this protein indicate that tPA could be a new therapeutic target for pancreatic cancer. Although a few studies have addressed the mechanisms through which tPA may participate in invasion and angiogenesis, 38,40,41 little is known about the molecular mechanisms involved in tPA-mediated cell proliferation. Here, we provide the first evidence that tPA induces pancreatic cancer cell proliferation through the activation of the ERK1/2 signaling pathway and, most importantly, that this effect is independent of tPA catalytic activity and mediated by AnxA2 and EGFR.…”

Section: Discussionmentioning

confidence: 99%

“…37 Moreover, tPA is required for in vitro invasiveness 38 and in vivo tumor growth and angiogenesis. 39,40 We have also found, using a murine model of pancreatic cancer, that the inactivation of tPA is associated with an increase in survival, 39 suggesting a relevant role of this protease in tumor progression. This effect is associated with a marked reduction in cell proliferation in ductal tumors as well as with reduced angiogenesis.…”

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confidence: 89%

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Tissue Plasminogen Activator Induces Pancreatic Cancer Cell Proliferation by a Non-Catalytic Mechanism That Requires Extracellular Signal-Regulated Kinase 1/2 Activation through Epidermal Growth Factor Receptor and Annexin A2

Ortiz-Zapater

Peiró

Roda

et al. 2007

The American Journal of Pathology

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Tissue plasminogen activator (tPA) is overexpressed in pancreatic ductal carcinoma and is involved in tumor progression. This effect is probably mediated through the activation of angiogenesis, cell invasion, and cell proliferation. Previous studies support the notion that the effects of tPA on cell invasion require its proteolytic activity. Here, we report the molecular mechanism responsible for the proliferative effects of tPA on pancreatic tumor cells. tPA activates the extracellular signal-regulated kinase 1/2 signaling pathway in a manner that is independent of its catalytic activity. We also show that at least two membrane receptors, epidermal growth factor receptor and annexin A2, which are overexpressed in pancreatic cancer, are involved in the transduction of tPA signaling in pancreatic tumors. This observation suggests the establishment of an amplification loop in tumor cell proliferation. Double immunofluorescence experiments showed co-localization of tPA/epidermal growth factor receptor and tPA/annexin A2 in pancreas cancer cells. These results add novel insights into the non-catalytic functions of tPA in cancer and the molecular mechanisms behind the effects of this protease on cell proliferation, including a role for epidermal growth factor receptor. (Am J Pathol 2007, 170

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“…MVD and EA have been experimentally proposed to be biomarkers associated with biological aggressiveness and clinical outcome in animal and human malignancies. In regards to pancreatic cancer, it has been established that angiogenesis has a role in its development and progression (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). In addition, Ki-67 expression is an important parameter for biological aggressiveness and prognosis in tumour tissue; Ki-67 antigens are initially expressed in S-phase and increase throughout S-and G 2 -phase until they reach their peak expression during mitosis.…”

Section: Introductionmentioning

confidence: 99%

Microvascular density and endothelial area correlate with Ki-67 proliferative index in surgically-treated pancreatic ductal adenocarcinoma patients

et al. 2015

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Abstract. Previous experimental and clinical data have indicated that tumour cell proliferation is associated with angiogenesis; in addition, an increased microvascular density (MVD) of tumours has been associated with poor prognosis in solid and haematological malignancies. However, limited data exists regarding the association between tumour cell proliferation and angiogenesis in primary tumour tissue from pancreatic ductal adenocarcinoma (PDAC) patients; therefore, the present study aimed to investigate this association. A series of 31 PDAC patients with stage Tumour (T) [2][3] Node (N) 0-1 Metastasis (M) 0 were recruited into the present study and subsequently underwent surgery. PDAC tissue and adjacent normal tissue (ANT), resected during surgery, were evaluated using immunohistochemistry and image analysis methods to determine MVD, endothelial area (EA) and Ki-67 expression, which is an indicator of cell proliferation rate. The results demonstrated a correlation between the above parameters with each other as well as the main clinico-pathological features of PDAC. Significant differences were identified in MVD, EA and Ki-67 proliferation index between PDAC and ANT. It was demonstrated that MVD, EA and Ki-67 proliferation index were significantly correlated with each other in tumour tissue (r=0.69-0.81; P=0.001-0.003). However, no other significant correlations were identified. These data therefore suggested that angiogenesis and cell proliferation rate were significantly increased in PDAC compared with ANT, which provides a biological basis for the potential use of novel combinations of angiogenesis inhibitors and anti-proliferative chemotherapeutic drugs in the treatment of PDAC.

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Tissue plasminogen activator is required for the growth, invasion, and angiogenesis of pancreatic tumor cells

Cited by 63 publications

References 48 publications

Dynamic changes in messenger RNA profiles of bovine endometrium during the oestrous cycle

Dynamic changes in messenger RNA profiles of bovine endometrium during the oestrous cycle

Tissue Plasminogen Activator Induces Pancreatic Cancer Cell Proliferation by a Non-Catalytic Mechanism That Requires Extracellular Signal-Regulated Kinase 1/2 Activation through Epidermal Growth Factor Receptor and Annexin A2

Microvascular density and endothelial area correlate with Ki-67 proliferative index in surgically-treated pancreatic ductal adenocarcinoma patients

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