Lorella Vecchio

Rearrangement of nuclear ribonucleoprotein (RNP)-containing structures during apoptosis and transcriptional arrest

Abstract The aim of this paper is to review the data in the literature concerning ribonucleoprotein components during apoptosis, where a major rearrangement of RNPs takes place. In parallel with chromatin changes, the nucleoplasmic constituents (perichromatin fibrils; perichromatin granules; interchromatin granules and nuclear bodies) as well as the nucleoli aggregate into heterogeneous clusters called HERDS, in the interchromatin space. Later, these RNP‐containing structures are extruded from the nucleus and leave the cell within cytoplasmic blebs. We propose also a role for HERDS as markers of irreversible transcriptional arrest.

Interactions between bone marrow stromal microenvironment and B-chronic lymphocytic leukemia cells: any role for Notch, Wnt and Hh signaling pathways?

B-cell chronic lymphocytic leukemia (CLL), which is the most common lymphoproliferative disorder, displays characteristics consistent with a defect in programmed cell death and exhibit prolonged survival of affected cells in vivo. When recovered from peripheral blood or lymphoid tissues of patients and cultured in vitro, CLL malignant cells rapidly undergo spontaneous apoptosis. CLL B-cells co-culture with different adherent cell types, collectively referred to as stromal cells, induces leukemia cell survival, migration, and drug resistance. In addition, such survival-promoting microenvironments can rescue leukemia cells from cytotoxic therapy, giving way to disease relapse. Quite surprisingly considering that many anti-cancer drugs, including γ-secretase inhibitors, Cyclopamine and Quercetin, were reported to block Notch, Wnt, and Hedgehog anti-apoptotic signaling pathways respectively, the link between the latter anti-apoptotic pathways and bone marrow stromal cells in CLL has been pointed out only recently. Data concerning the pathogenesis of CLL have been critically reviewed in regards to the growing body of evidence indicating deregulations of Notch, Wnt and Hedgehog anti-apoptotic signaling pathways in the stromal microenvironment of affected cells.

DADLE induces a reversible hibernation-like state in HeLa cells.

Abstract[d-Ala(2)-d-Leu(5)-Enkephalin] (DADLE) can induce hibernation when injected into ground squirrels in summer and is able to increase the survival time of explanted organs such as liver and lung. Since cell metabolism is a target of this peptide, we have treated HeLa cells with DADLE and investigated its possible effect on transcription and proliferation as well as the resumption of metabolic activity after treatment. The labelling for Pol I, Pol II and for splicing factors such as snRNPs and SC-35 decreased after treatment as did the nucleolar labelling for UBF. In treated cells, several spherical nuclear bodies were found to be labelled for hnRNPs. In parallel, the number of proliferating cells decreased after treatment with DADLE. After recovery, there was a gradual resumption of cell function: transcription and splicing factors had a distribution similar to that of controls; proliferation resumed; nuclear bodies, representing storage sites for RNPs, disappeared.

Signaling pathways in breast cancer: Therapeutic targeting of the microenvironment

Breast cancer is the most common cancer in women worldwide. Understanding the biology of this malignant disease is a prerequisite for selecting an appropriate treatment. Cell cycle alterations are seen in many cancers, including breast cancer. Newly popular targeted agents in breast cancer include cyclin dependent kinase inhibitors (CDKIs) which are agents inhibiting the function of cyclin dependent kinases (CDKs) and agents targeting proto-oncogenic signaling pathways like Notch, Wnt, and SHH (Sonic hedgehog). CDKIs are categorized as selective and non-selective inhibitors of CDK. CDKIs have been tried as monotherapy and combination therapy. The CDKI Palbocyclib is now a promising therapeutic in breast cancer. This drug recently entered phase III trial for estrogen receptor (ER) positive breast cancer after showing encouraging results in progression free survival in a phase II trials. The tumor microenvironment is now recognized as a significant factor in cancer treatment response. The tumor microenvironment is increasingly considered as a target for combination therapy of breast cancer. Recent findings in the signaling pathways in breast cancer are herein summarized and discussed. Furthermore, the therapeutic targeting of the microenvironment in breast cancer is also considered.

Signaling pathways in chronic myeloid leukemia and leukemic stem cell maintenance: Key role of stromal microenvironment

Chronic myeloid leukemia (CML) is caused by the malignant transformation of hematopoietic stem cells in leukemic stem cells. From the introduction of the anti-cancer drug imatinib, the therapy of CML has been positively transformed. However, following treatment most patients display a residual CML disease attributed to the presence of quiescent leukemic stem cells intrinsically resistant to imatinib. Considering that the later cancer cells lose their chemoresistance in vitro, it appears that the stromal microenvironment plays a crucial role in CML-affected cell chemoresistance. In the present review, we summarize and discuss the recent findings on signaling pathways through which stromal cells sustain CML leukemogenesis, as well as leukemic stem cell maintenance and chemoresistance.

Normal hematopoiesis and hematologic malignancies: Role of canonical Wnt signaling pathway and stromal microenvironment

Wnts are a family of evolutionary-conserved secreted signaling molecules critically involved in a variety of developmental processes and in cell fate determination. A growing body of evidence suggests that Wnt signaling plays a crucial role in the influence of bone marrow stromal microenvironment on the balance between hematopoietic stem cell self-renewal and differentiation. Emerging clinical and experimental evidence also indicates Wnt signaling involvement in the disruption of the latter balance in hematologic malignancies, where the stromal microenvironment favors the homing of cancer cells to the bone marrow, as well as leukemia stem cell development and chemoresistance. In the present review, we summarize and discuss the role of the canonical Wnt signaling pathway in normal hematopoiesis and hematologic malignancies, with regard to recent findings on the stromal microenvironment involvement in these process and diseases.

The effect of the enkephalin DADLE on transcription does not depend on opioid receptors

Abstract[D-Ala2,D-Leu5] enkephalin (DADLE) is a synthetic peptide capable of inducing a hibernation-like state in mammals in vivo and in cultured cells in vitro. The effects of DADLE seem to be due to its binding to opioid receptors; however, it inhibits the growth of LNCaP cells, devoid of opioid receptors. We have investigated the effects of DADLE on this cell line using transmission electron microscopy, immunocytochemistry and cytometry, in order to elucidate the general mechanism(s) by which this enkephalin affects cell metabolism. We demonstrated that, similar to cell lines provided with opioid receptors, in LNCaP cells DADLE induces structural modifications of cytoplasmic and nuclear constituents, as well as a decrease in transcription and proliferation. However, DADLE does not provoke an increase in apoptotic or necrotic cell fraction, and, after removing the enkephalin from the culture medium, all effects disappear. We also demonstrated that DADLE molecules enter the cytoplasm and the nucleus of LNCaP cells, mostly binding to perichromatin fibrils and dense fibrillar component, where transcription and early splicing of pre-mRNAs and pre-rRNAs occur. In conclusion, our data demonstrate that the effect of DADLE on transcription and on cultured cells does not depend on opioid receptors. DADLE can, therefore, be envisaged as an extremely promising molecule to be used for inducing a reversible hypometabolic state in various cultured cells, without provoking cell damage or death.

Importance of epigenetic changes in cancer etiology, pathogenesis, clinical profiling, and treatment: what can be learned from hematologic malignancies?

Epigenetic alterations represent a key cancer hallmark, even in hematologic malignancies (HMs) or blood cancers, whose clinical features display a high inter-individual variability. Evidence accumulated in recent years indicates that inactivating DNA hypermethylation preferentially targets the subset of polycomb group (PcG) genes that are regulators of developmental processes. Conversely, activating DNA hypomethylation targets oncogenic signaling pathway genes, but outcomes of both events lead in the overexpression of oncogenic signaling pathways that contribute to the stem-like state of cancer cells. On the basis of recent evidence from population-based, clinical and experimental studies, we hypothesize that factors associated with risk for developing a HM, such as metabolic syndrome and chronic inflammation, trigger epigenetic mechanisms to increase the transcriptional expression of oncogenes and activate oncogenic signaling pathways. Among others, signaling pathways associated with such risk factors include pro-inflammatory nuclear factor κB (NF-κB), and mitogenic, growth, and survival Janus kinase (JAK) intracellular non-receptor tyrosine kinase-triggered pathways, which include signaling pathways such as transducer and activator of transcription (STAT), Ras GTPases/mitogen-activated protein kinases (MAPKs)/extracellular signal-related kinases (ERKs), phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), and β-catenin pathways. Recent findings on epigenetic mechanisms at work in HMs and their importance in the etiology and pathogenesis of these diseases are herein summarized and discussed. Furthermore, the role of epigenetic processes in the determination of biological identity, the consequences for interindividual variability in disease clinical profile, and the potential of epigenetic drugs in HMs are also considered.

Developmental pathways associated with cancer metastasis: Notch, Wnt, and Hedgehog

Master developmental pathways, such as Notch, Wnt, and Hedgehog, are signaling systems that control proliferation, cell death, motility, migration, and stemness. These systems are not only commonly activated in many solid tumors, where they drive or contribute to cancer initiation, but also in primary and metastatic tumor development. The reactivation of developmental pathways in cancer stroma favors the development of cancer stem cells and allows their maintenance, indicating these signaling pathways as particularly attractive targets for efficient anticancer therapies, especially in advanced primary tumors and metastatic cancers. Metastasis is the worst feature of cancer development. This feature results from a cascade of events emerging from the hijacking of epithelial-mesenchymal transition, angiogenesis, migration, and invasion by transforming cells and is associated with poor survival, drug resistance, and tumor relapse. In the present review, we summarize and discuss experimental data suggesting pivotal roles for developmental pathways in cancer development and metastasis, considering the therapeutic potential. Emerging targeted antimetastatic therapies based on Notch, Wnt, and Hedgehog pathways are also discussed.

Stromal control of chronic lymphocytic leukemia cells

License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Research and Reports in Biology 2013:4 23–32 Research and Reports in Biology Dovepress