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.

Chemotherapy-induced neutropenia elicits metastasis formation in mice by promoting proliferation of disseminated tumor cells.

Chemotherapy is the standard of care for most malignancies. Its tumor debulking effect in adjuvant or neoadjuvant settings is unquestionable, although secondary effects have been reported that paradoxically promote metastasis. Chemotherapy affects the hematopoietic precursors leading to myelosuppression, with neutropenia being the main hematological toxicity induced by cytotoxic therapy.

The PARP1 Inhibitor AZD5305 Impairs Ovarian Adenocarcinoma Progression and Visceral Metastases in Patient-derived Xenografts Alone and in Combination with Carboplatin.

Unlabelled: PARP inhibitors (PARPi) have changed the management of patients with ovarian cancer and their effectiveness has been demonstrated especially in homologous recombination repair-deficient tumors. These first-generation drugs target PARP1, but also PARP2 and other family members potentially responsible for adverse effects that limit their therapeutic potential and restrict their use in combination with chemotherapeutic agents. We investigated ovarian cancer patient-derived xenografts (OC-PDXs) to assess whether malignant progression could be impaired by a novel inhibitor selective for PARP1 (AZD5305) and to assess the potential of its combination with carboplatin (CPT), the standard-of-care for patients with ovarian cancer.

Differential angiogenesis of bone and muscle endothelium in aging and inflammatory processes.

Different tissues have different endothelial features, however, the implications of this heterogeneity in pathological responses are not clear yet. "Inflamm-aging" has been hypothesized as a possible trigger of diseases, including osteoarthritis (OA) and sarcopenia, often present in the same patient. To highlight a possible contribution of organ-specific endothelial cells (ECs), we compare ECs derived from bone and skeletal muscle of the same OA patients.

The DNA-PK Inhibitor AZD7648 Sensitizes Patient-Derived Ovarian Cancer Xenografts to Pegylated Liposomal Doxorubicin and Olaparib Preventing Abdominal Metastases.

Ovarian cancer is the deadliest gynecologic cancer, with a 5-year survival rate of 30%, when the disease has spread throughout the peritoneal cavity. We investigated the efficacy to delay disease progression by the DNA-dependent protein kinase (DNA-PK) inhibitor AZD7648, administered in combination with two of the therapeutic options for patient management: either pegylated liposomal doxorubicin (PLD) or the PARP inhibitor olaparib. Patient-derived ovarian cancer xenografts (OC-PDX) were transplanted subcutaneously to evaluate the effect of treatment on tumor growth, or orthotopically in the peritoneal cavity to evaluate the effect on metastatic spread.

VEGF pathway inhibition potentiates PARP inhibitor efficacy in ovarian cancer independent of BRCA status.

Poly ADP-ribose polymerase inhibitors (PARPi) have transformed ovarian cancer (OC) treatment, primarily for tumours deficient in homologous recombination repair. Combining VEGF-signalling inhibitors with PARPi has enhanced clinical benefit in OC. To study drivers of efficacy when combining PARP inhibition and VEGF-signalling, a cohort of patient-derived ovarian cancer xenografts (OC-PDXs), representative of the molecular characteristics and drug sensitivity of patient tumours, were treated with the PARPi olaparib and the VEGFR inhibitor cediranib at clinically relevant doses.

Establishment of patient-derived tumor xenograft models of mucinous ovarian cancer.

Mucinous ovarian carcinoma (mEOC) represents a rare subtype of epithelial ovarian cancer, accounting for 3-4% of all ovarian carcinomas. The rarity of this tumor type renders both the preclinical and clinical research compelling. Very few preclinical and models exist.

Soluble stroma-related biomarkers of pancreatic cancer.

The clinical management of pancreatic ductal adenocarcinoma (PDAC) is hampered by the lack of reliable biomarkers. This study investigated the value of soluble stroma-related molecules as PDAC biomarkers. In the first exploratory phase, 12 out of 38 molecules were associated with PDAC in a cohort of 25 PDAC patients and 16 healthy subjects.

Tumor progression and metastatic dissemination in ovarian cancer after dose-dense or conventional paclitaxel and cisplatin plus bevacizumab.

The efficacy of therapeutic regimens incorporating weekly or every-3-weeks paclitaxel (PTX) for ovarian cancer is debated. We investigated the addition of bevacizumab in regimens of chemotherapy with different PTX doses and schedules in preclinical models. Treatments were cisplatin (DDP) with weekly PTX (conventional), or dose-dense-equi (every other day to the conventional cumulative dose), or dose-dense-high (total dose 1.

Targeting melanoma stem cells with the Vitamin E derivative δ-tocotrienol.

The prognosis of metastatic melanoma is very poor, due to the development of drug resistance. Cancer stem cells (CSCs) may play a crucial role in this mechanism, contributing to disease relapse. We first characterized CSCs in melanoma cell lines.

Modeling Cytostatic and Cytotoxic Responses to New Treatment Regimens for Ovarian Cancer.

The margin for optimizing polychemotherapy is wide, but a quantitative comparison of current and new protocols is rare even in preclinical settings. reconstruction of the proliferation process and the main perturbations induced by treatment provides insight into the complexity of drug response and grounds for a more objective rationale to treatment schemes. We analyzed 12 treatment groups in trial on an ovarian cancer xenograft, reproducing current therapeutic options for this cancer including one-, two-, and three-drug schemes of cisplatin (DDP), bevacizumab (BEV), and paclitaxel (PTX) with conventional and two levels ("equi" and "high") of dose-dense schedules.

Trypsinogen 4 boosts tumor endothelial cells migration through proteolysis of tissue factor pathway inhibitor-2.

Proteases contribute to cancer in many ways, including tumor vascularization and metastasis, and their pharmacological inhibition is a potential anticancer strategy. We report that human endothelial cells (EC) express the trypsinogen 4 isoform of the serine protease 3 (PRSS3), and lack both PRSS2 and PRSS1. Trypsinogen 4 expression was upregulated by the combined action of VEGF-A, FGF-2 and EGF, angiogenic factors representative of the tumor microenvironment.

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.

Sunitinib prevents cachexia and prolongs survival of mice bearing renal cancer by restraining STAT3 and MuRF-1 activation in muscle.

Tyrosine kinase inhibitors, affecting angiogenesis, have shown therapeutic efficacy in renal cell carcinoma (RCC). The increased overall survival is not fully explained by their anti-tumor activity, since these drugs frequently induce disease stabilization rather than regression. RCC patients frequently develop cachectic syndrome.

Patient-derived ovarian tumor xenografts recapitulate human clinicopathology and genetic alterations.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. On the basis of its histopathology and molecular-genomic changes, ovarian cancer has been divided into subtypes, each with distinct biology and outcome. The aim of this study was to develop a panel of patient-derived EOC xenografts that recapitulate the molecular and biologic heterogeneity of human ovarian cancer.

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.

Paclitaxel enhances therapeutic efficacy of the F8-IL2 immunocytokine to EDA-fibronectin-positive metastatic human melanoma xenografts.

The selective delivery of bioactive agents to tumors reduces toxicity and enhances the efficacy of anticancer therapies. In this study, we show that the antibody F8, which recognizes perivascular and stromal EDA-fibronectin (EDA-Fn), when conjugated to interleukin-2 (F8-IL2) can effectively inhibit the growth of EDA-Fn-expressing melanomas in combination with paclitaxel. We obtained curative effects with paclitaxel administered before the immunocytokine.

Dual targeting of tumor and endothelial cells by gonadotropin-releasing hormone agonists to reduce melanoma angiogenesis.

We showed previously that GnRH receptors are expressed in melanoma cells; their activation reduces cell growth and metastatic behavior. Here, we investigated whether GnRH agonists might affect the expression of genes involved in melanoma progression. By genome-wide transcriptomic and real-time PCR analysis, we first observed that GnRH agonists decrease the expression of the pro-angiogenic factor vascular endothelial growth factor (VEGF) (all isoforms) in BLM melanoma cells.

Protease-activated receptor-1 (PAR-1) promotes the motility of human melanomas and is associated to their metastatic phenotype.

Protease-activated receptor-1 (PAR-1) is a unique G-protein-coupled receptor belonging to the protease-activated receptor family. Its activation leads to downstream signaling events that launch a variety of cellular responses related to tumor progression. PAR-1 expression has been associated to a variety of human cancers, and our previous studies reveal a high PAR-1 expression in melanoma specimens as compared to common nevi.

Tumor-host interaction in the optimization of paclitaxel-based combination therapies with vascular targeting compounds.

Targeting of the tumor stroma, including the tumor vasculature, represents a new frontier in the treatment of malignancy. Preclinical studies and clinical experiences have established that stroma-directed novel agents must be combined with conventional therapies in order to achieve relevant therapeutic efficacy. Here we review our preclinical experience on combinations of paclitaxel with a tyrosine kinase receptor inhibitor of angiogenesis (SU6668) and a vascular disrupting agent (VDA, ZD6126), and discuss the critical factors that determine the outcome of these treatments.

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.

Gene expression correlating with response to paclitaxel in ovarian carcinoma xenografts.

We have investigated gene expression profiles of human ovarian carcinomas in vivo during Taxol(R) (paclitaxel) treatment and observed a difference in expression. Nude mice bearing 1A9 or 1A9PTX22 xenografts were given 60 mg/kg of paclitaxel. Therapeutic efficacy was achieved for 1A9, while 1A9PTX22 did not respond.

All-trans retinoic acid modulates microvascular endothelial cell hemostatic properties.

Background And Objectives: All-trans retinoic acid (ATRA) is an anti-tumor agent capable of controlling the hypercoagulable state associated with malignancy. Among hemostasis-regulating functions, ATRA modulates the procoagulant and fibrinolytic properties of endothelial cells (EC) from large vessels (HUVEC). In this study we investigated whether ATRA may affect the same activities of EC derived from microvessels (HMEC-1 cell line).