Fibronectin fragments generated by pancreatic trypsin act as endogenous inhibitors of pancreatic tumor growth.

Background: The pancreatic microenvironment has a defensive role against cancer but it can acquire tumor-promoting properties triggered by multiple mechanisms including alterations in the equilibrium between proteases and their inhibitors. The identification of proteolytic events, targets and pathways would set the basis for the design of new therapeutic approaches.

Methods And Results: Here we demonstrate that spheroids isolated from human and murine healthy pancreas and co-transplanted orthotopically with pancreatic ductal adenocarcinoma (PDAC) in mouse pancreas inhibited tumor growth.

Tumor vascular remodeling by thrombospondin-1 enhances drug delivery and antineoplastic activity.

The disorganized and inefficient tumor vasculature is a major obstacle to the delivery and efficacy of antineoplastic treatments. Antiangiogenic agents can normalize the tumor vessels, improving vessel function and boosting the distribution and activity of chemotherapy. The type III repeats (T3R) domain of thrombospondin-1 contains different potential antiangiogenic sequences.

CCN-Based Therapeutic Peptides Modify Pancreatic Ductal Adenocarcinoma Microenvironment and Decrease Tumor Growth in Combination with Chemotherapy.

The prominent desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) is a determinant factor in tumor progression and a major barrier to the access of chemotherapy. The PDAC microenvironment therefore appears to be a promising therapeutic target. CCN2/CTGF is a profibrotic matricellular protein, highly present in the PDAC microenvironment and associated with disease progression.

Antimetastatic and antiangiogenic activity of trabectedin in cutaneous melanoma.

Trabectedin is a marine-derived antineoplastic drug. Besides targeting the cancer cells, trabectedin has a peculiar activity on the tumor microenvironment with marked effects on the vasculature and the immune response. Because a favorable microenvironment is a key factor in the progression of cutaneous melanoma, we hypothesized that trabectedin might affect the growth and metastasis of this highly aggressive cancer.

The calcium-binding type III repeats domain of thrombospondin-2 binds to fibroblast growth factor 2 (FGF2).

Thrombospondin (TSP)-1 and TSP-2 share similar structures and functions, including a remarkable antiangiogenic activity. We have previously demonstrated that a mechanism of the antiangiogenic activity of TSP-1 is the interaction of its type III repeats domain with fibroblast growth factor-2 (FGF2), affecting the growth factor bioavailability and angiogenic activity. Since the type III repeats domain is conserved in TSP-2, this study aimed at investigating whether also TSP-2 retained the ability to interact with FGF2.

Expression of thrombospondin-1 by tumor cells in patient-derived ovarian carcinoma xenografts.

Purpose: Thrombospondin-1 (TSP-1), a major regulator of cell interaction with the environment, is often deregulated in cancers, including ovarian carcinoma. Both the tumor and the host cells can release TSP-1 in the tumor microenvironment. The relative contribution of the two sources in determining TSP-1 levels in ovarian cancer remains to be elucidated.

Thrombospondin-1 is part of a Slug-independent motility and metastatic program in cutaneous melanoma, in association with VEGFR-1 and FGF-2.

Differently from most transformed cells, cutaneous melanoma expresses the pleiotropic factor thrombospondin-1 (TSP-1). Herein, we show that TSP-1 (RNA and protein), undetectable in four cultures of melanocytes and a RGP melanoma, was variously present in 13 cell lines from advanced melanomas or metastases. Moreover, microarray analysis of 55 human lesions showed higher TSP-1 expression in primary melanomas and metastases than in common and dysplastic nevi.

Antiangiogenic activity of trabectedin in myxoid liposarcoma: involvement of host TIMP-1 and TIMP-2 and tumor thrombospondin-1.

Trabectedin is a marine natural product, approved in Europe for the treatment of soft tissue sarcoma and relapsed ovarian cancer. Clinical and experimental evidence indicates that trabectedin is particularly effective against myxoid liposarcomas where response is associated to regression of capillary networks. Here, we investigated the mechanism of the antiangiogenic activity of trabectedin in myxoid liposarcomas.

Pharmacokinetics and antineoplastic activity of galectin-1-targeting OTX008 in combination with sunitinib.

Purpose: OTX008 is a galectin-1-targeting compound, currently undergoing a phase I clinical trial. This study aimed at investigating OTX008 pharmacokinetics (PK) and antineoplastic activity.

Methods: Pharmacokinetics and activity of OTX008 were analyzed in the human ovarian carcinoma A2780-1A9 and glioblastoma U87MG xenografted in nude mice.

Inhibition of SIRT2 potentiates the anti-motility activity of taxanes: implications for antineoplastic combination therapies.

Taxanes are potent inhibitors of cell motility, a property implicated in their antiangiogenic and antimetastatic activity and unrelated to their antiproliferative effect. The molecular mechanism of this anti-motility activity is poorly understood. In this study, we found that paclitaxel induced tubulin acetylation in endothelial and tumor cells, at concentrations that affected cell motility but not proliferation (10(-8) to 10(-9) M, for 4 hours).

Vascular disrupting activity of tubulin-binding 1,5-diaryl-1H-imidazoles.

Highly cytotoxic 1,5-diaryl-1H-imidazoles were studied to clarify the relationship between cytotoxicity and activity as vascular disrupting agents (VDA). All the compounds disorganized the tubulin cytoskeleton, affected endothelial cell morphology and capillary formation in vitro, and caused vessel shutdown and tumor necrosis in vivo, thus confirming their vascular disrupting properties. Nonetheless, the substitution patterns on the imidazole ring, responsible for greater interaction energy with tubulin and higher cytotoxicity, were not associated to greater vascular disrupting activity.

Bioavailability of VEGF in tumor-shed vesicles depends on vesicle burst induced by acidic pH.

Tumor angiogenesis is regulated by a dynamic cross-talk between tumor cells and the host microenvironment. Because membrane vesicles shed by tumor cells are known to mediate several tumor-host interactions, we determined whether vesicles might also stimulate angiogenesis. Vesicles shed by human ovarian carcinoma cell lines CABA I and A2780 stimulated the motility and invasiveness of endothelial cells in vitro.

The vascular targeting property of paclitaxel is enhanced by SU6668, a receptor tyrosine kinase inhibitor, causing apoptosis of endothelial cells and inhibition of angiogenesis.

Purpose: Different antiangiogenic approaches have been proposed in cancer treatment where therapeutic efficacy has been shown with the addition of cytotoxic agents. Here, we used SU6668, a small-molecule receptor tyrosine kinase inhibitor, to investigate the combinatorial effect with paclitaxel on the cellular populations of the developing vasculature.

Experimental Design: The effect of this combination was evaluated in vitro in a 72-hour proliferation assay on human umbilical vein endothelial cells (HUVEC) and human microvascular endothelial cells derived from lungs, endothelial cells, aortic smooth muscle cells, and human ovarian carcinoma cells sensitive (1A9) and resistant (1A9-PTX22) to paclitaxel.

Potential antagonism of tubulin-binding anticancer agents in combination therapies.

ZD6126 is a vascular targeting agent, developed for the treatment of solid tumors. In vivo, ZD6126 is rapidly converted into the tubulin-binding agent N-acetylcolchinol. We have previously reported that in vitro N-acetylcolchinol disrupts microtubules and induces rapid changes in endothelial cell morphology, which in a tumor would lead to a rapid loss of tumor vessel integrity and subsequent extensive tumor necrosis.

Antiangiogenic properties of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin: an orally bioavailable heat shock protein 90 modulator.

Purpose: The purpose of this study was to investigate the antiangiogenic properties of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG; NSC707545), a water-soluble benzoquinone ansamycin.

Experimental Design: The activity of 17-DMAG, in vivo, was evaluated for inhibition of fibroblast growth factor (FGF)-2-induced angiogenesis in s.c.

Antiangiogenic activity of aplidine, a new agent of marine origin.

The antineoplastic compound aplidine, a new marine-derived depsipeptide, has shown preclinical activity in vitro on haematological and solid tumour cell lines. It is currently in early phase clinical trials. The exact mechanism of action of this anticancer agent still needs to be clarified.

Aplidine, a new anticancer agent of marine origin, inhibits vascular endothelial growth factor (VEGF) secretion and blocks VEGF-VEGFR-1 (flt-1) autocrine loop in human leukemia cells MOLT-4.

The mechanism by which aplidine, a marine natural product in early clinical development as an anticancer agent, induces cell growth inhibition and apoptosis has been investigated in the human leukemia cell line MOLT-4. This cell line is characterized not only by the ability to secrete VEGF, but also for the presence on its surface of the VEGF receptor-1 (VEGFR-1). Previous studies from our laboratory concerned with evaluating early changes in gene expression induced by aplidine in MOLT-4 cells have shown that the drug decreases the expression of VEGFR-1 (Marchini et al.

Antiangiogenic and antitumor activity of IDN 5390, a new taxane derivative.

Purpose: We previously reported that paclitaxel, a microtubule-stabilizing drug, inhibited angiogenesis, mainly by inhibiting endothelial cell motility (D. Belotti et al., Clin.

Shedding of the matrix metalloproteinases MMP-2, MMP-9, and MT1-MMP as membrane vesicle-associated components by endothelial cells.

Production of matrix-degrading proteases, particularly matrix metalloproteinases (MMPs), by endothelial cells is a critical event during angiogenesis, the process of vessel neoformation that occurs in normal and pathological conditions. MMPs are known to be highly regulated at the level of synthesis and activation, however, little is known about the regulation of MMP secretion by endothelial cells. We found that cultured human umbilical vein endothelial cells shed vesicles (300 to 600 nm) originating from localized areas of the cell plasma membrane, as revealed by ultrastructural analysis.

p73 Overexpression increases VEGF and reduces thrombospondin-1 production: implications for tumor angiogenesis.

Tumor neovascularization is controlled by a balance between positive and negative effectors, whose production can be regulated by oncogenes and tumor suppressor genes. The aim of this study was to investigate whether the angiogenic potential of tumors could also be controlled by p73, a gene homologous to the tumor suppressor p53, whose involvement in tumor angiogenesis is known. We have studied the production of proangiogenic (VEGF, FGF-2, PIGF and PDGF) and antiangiogenic (TSP-1) factors in two p73 overexpressing clones obtained from the human ovarian carcinoma cells A2780.

Inhibition of matrix metalloproteinases by over-expression of tissue inhibitor of metalloproteinase-2 inhibits the growth of experimental hemangiomas.

Inhibitors of proteases prevent tumor-associated matrix degradation, affecting tumor growth, angiogenesis and metastasis. Our study was designed to investigate the effect of inhibition of matrix metalloproteinases (MMPs) on the growth of experimental hemangiomas, using the model of murine endothelioma eEnd.1 cells.

Endothelin-1 induces an angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo.

The endothelial cell-derived endothelin-1 (ET-1) is a potent mitogen for endothelial cells, vascular smooth muscle cells, and tumor cells. In this study, we analyzed the role of ET-1 on human umbilical vein endothelial cell (HUVEC) phenotype related to different stages of angiogenesis. ET-1 promoted HUVEC proliferation, migration, and invasion in a dose-dependent manner.

Posttranscriptional stimulation of endothelial cell matrix metalloproteinases 2 and 1 by endothelioma cells.

Matrix metalloproteinases (MMPs) play a critical role in the development of hemangioma-like vascular tumors in mice injected with murine eEnd.1 endothelioma cells. The current study was designed to (a) characterize the presence of MMPs in the vascular tumor, (b) define whether these MMPs originate from the transformed cells or from the recruited stromal cells and (c) study the stimulatory effect of eEnd.