Papers by Antonio Mazzocca
BMC Cancer, Jan 27, 2014
Background: Thrombocytopenia has been reported to be associated with small size HCCs, and thrombo... more Background: Thrombocytopenia has been reported to be associated with small size HCCs, and thrombocytosis to be associated with large size HCCs. The aim was to examine the effects of platelets in relation to HCC cell growth. Methods: The effects of time-expired pooled normal human platelets were examined on human HCC cell line growth and invasion. Results: Blood platelet numbers increased with increasing HCC tumor size and portal vein invasion. Platelet extracts enhanced cell growth in 4 human HCC cell lines, as well as cell migration, medium AFP levels and decreased apoptosis. Cell invasion was significantly enhanced, using a Matrigel-coated trans-well membrane and3D (Real-Time Imaging) invasion assay. Western blots showed that platelets caused enhanced phospho-ERK and phospho-JNK signaling and anti-apoptotic effect with increase of Bcl-xL (anti-apoptotic marker) and decrease of Bid (pro-apoptotic marker) levels. Their growth effects were blocked by a JNK inhibitor. Conclusions: Platelets stimulated growth and invasion of several HCC cell lines in vitro, suggesting that platelets or platelet growth factors could be a potential pharmacological target.
Medical Hypotheses, Jul 1, 2021
Since Nixon famously declared war on cancer in 1971, trillions of dollars have been spent on canc... more Since Nixon famously declared war on cancer in 1971, trillions of dollars have been spent on cancer research but the life expectancy for most forms of cancer is still poor. There are many reasons for the partial success of cancer translational research. One of these can be the predominance of certain paradigms that potentially narrowed the vision in interpreting cancer. The main paradigm to explain carcinogenesis is based on DNA mutations, which is well interpreted by the somatic mutation theory (SMT). However, a different theory claims that cancer is instead a tissue disease as proposed by the Tissue Organization Field Theory (TOFT). Here, we propose new hypotheses to explain the origin and pathogenesis of cancer. In this perspective, the systemic-evolutionary theory of cancer (SETOC) is discussed as well as how the microenvironment affects the adaptation of transformed cells and the reversion to a unicellular-like or embryo-like phenotype.
Journal of Biological Chemistry, Mar 1, 2005
Current Medicinal Chemistry, May 1, 2009
The metastatic spread of cancer is still the major barrier to the treatment of this disease. Unde... more The metastatic spread of cancer is still the major barrier to the treatment of this disease. Understanding the molecular mechanisms underlying the metastatic process is of crucial importance to tune novel therapeutic strategies aimed at contrasting the dissemination of cancer. Metastasis is a sequential multistep process that ultimately leads to the cancer's outgrowth in a different organ from which it had originated. This clinically and experimentally involves the following steps: invasion of adjacent tissues, intravasation, transport of cancer cells through the circulatory system, arrest at a secondary site, extravasation and growth in a secondary organ. Additionally, tumor growth and metastasis depend on the ability of the tumor to induce its own blood supply through angiogenesis. Each of these steps can potentially be targeted by therapeutic agents, but the limited knowledge regarding the molecular events of metastasis makes most therapeutic strategies largely inefficient. However, important methodological advances have recently led to further insights into the biology of metastasis, thus raising the possibility of designing more appropriate pharmacological strategies to contrast the specific steps of the metastatic process. A variety of pharmacological approaches including inhibition of tumor invasion, angiogenesis, signal transduction pathways, and most recently the targeting of tumor stroma, are now under fervent development. Benefits and limits of these approaches, as well as, new therapeutic opportunities are herein discussed. Agents that limit any phase of the metastatic process may be therapeutically useful. Therefore, the future pharmacological challenge will be to combine drugs that target different aspects of this complex multistep process.
Journal of Hepatology, Apr 1, 2001
Journal of Hepatology, Sep 1, 2002
Migration of activated hepatic stellate cells (HSC) is a key event in the progression of liver fi... more Migration of activated hepatic stellate cells (HSC) is a key event in the progression of liver fibrosis. Little is known about transmembrane proteins involved in HSC motility. Tetraspanins (TM4SF) have been implicated in cell development, differentiation, motility and tumor cell invasion. We evaluated the expression and function of four TM4SF, namely CD9, CD81, CD63 and CD151, and their involvement in HSC migration, adhesion, and proliferation. All TM4SF investigated were highly expressed at the human HSC surface with different patterns of intracellular distribution. Monoclonal antibodies directed against the four TM4SF inhibited HSC migration induced by extracellular matrix proteins in both wound healing and haptotaxis assays. This inhibition was independent of the ECM substrates employed (collagen type I or IV, laminin), and was comparable to that obtained by incubating the cells with an anti-beta1 blocking mAb. Importantly, cell adhesion was unaffected by the incubation with the same antibodies. Co-immunoprecipitation studies revealed different patterns of association between the four TM4SF studied and beta1 integrin. Finally, anti-TM4SF antibodies did not affect HSC growth. These findings provide the first characterization of tetraspanins expression and of their role in HSC migration, a key event in liver tissue wound healing and fibrogenesis.
Journal of Hepatology, Aug 1, 2020
International Journal of Molecular Sciences, Dec 23, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Journal of Hepatology, Apr 1, 2003
Journal of Hepatology, Apr 1, 2001
Journal of Hepatology, Apr 1, 2002
Molecular Pharmacology, 2003
Hepatology, Jul 1, 2001
Expression of the integrin, alpha6beta1, a receptor for laminins, is associated with the progress... more Expression of the integrin, alpha6beta1, a receptor for laminins, is associated with the progression of hepatocellular carcinoma (HCC). The approach to investigating the alpha6beta1 integrin signaling in HCC cells was to express a deletion mutant of the beta4 integrin cytoplasmic domain (beta4-Deltacyt) in 2 HCC cell lines, HepG2 and Huh7. Expression of this mutant prevents formation of the alpha6beta1 heterodimer. As expected, adhesion of both the HepG2/beta4-Deltacyt and Huh7/beta4-Deltacyt transfectants to laminin, but not to collagen, was reduced compared with the mock transfectants. However, migration of the beta4-Deltacyt transfectants toward both collagen and laminin was inhibited, suggesting a role for alpha6beta1 in the signaling of migration. Migration of HCC cells requires mitogen-activated protein (MAP) kinase. The adhesion of the beta4-Deltacyt transfectants to collagen resulted in a substantial reduction in MAP kinase activation in comparison with the mock transfectants, although their ability to activate MAP kinase in response to epidermal growth factor (EGF) stimulation was not impaired. In addition, matrix adhesion of the beta4-Deltacyt transfectants did not stimulate the tyrosine phosphorylation of focal adhesion kinase (FAK), and this defect correlated with reduced binding of adaptor protein Grb2 to FAK. These results suggest that FAK tyrosine phosphorylation is dependent on alpha6beta1 expression, and that FAK-Grb2 association plays a central role in alpha6beta1-mediated activation of MAP kinase. Moreover, the expression of alpha6beta1 in HCC cells is necessary for FAK/MAP kinase-dependent migration.
Medical Oncology, Jul 22, 2020
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Papers by Antonio Mazzocca