Histology and histopathology Vol.27, nº 5 (2012)
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- PublicationOpen AccessActivation of alternative pathways of angiogenesis and involvement of stem cells following anti-angiogenesis treatment in glioma(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2012) Arbab, Ali S.Malignant gliomas are hypervascular tumors that are highly resistant to all the currently available multimodal treatments. Therefore, anti-angiogenic therapies targeting VEGF or VEGF receptors (VEGFRs) were designed and thought to be an effective tool for controlling the growth of malignant gliomas. However, recent results of early clinical trials using humanized monoclonal antibodies against VEGF (Bevacizumab), as well as small-molecule tyrosine kinase inhibitors that target different VEGF receptors (VEGFRs) (Vatalanib, Vandetanib, Sunitinib, Sorafenib, etc) alone or in combination with other therapeutic agents demonstrated differing outcomes, with the majority of reports indicating that glioma developed resistance to the employed anti-angiogenic treatments. It has been noted that continued anti-angiogenic therapy targeting only the VEGF-VEGFR system might affect pro-angiogenic factors other than VEGF, such as basic fibroblast growth factor (bFGF), stromal derived factor 1 (SDF-1) and Tie-2. These factors may in turn stimulate angiogenesis by mobilizing bone marrow derived precursor cells, such as endothelial progenitor cells (EPCs), which are known to promote angiogenesis and vasculogenesis. In this short review, the current antiangiogenic treatments, possible mechanisms of activation of alternative pathways of angiogenesis, and possible involvement of bone marrow derived progenitor cells in the failure of anti-angiogenic treatments are discussed
- PublicationOpen AccessExpression of the RNA-binding protein HuR and its clinical significance in human stage I and II lung adenocarcinoma(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2012) Lauriola, Libero; Granone, Pierluigi; Ramella, Sara; Lanza, Paola; Oreste Ranelletti, FrancoThe ubiquitously expressed RNA-binding protein Hu antigen (HuR) participates in the post-transcriptional regulation of mRNAs bearing U- and AU-rich sequences. Expression of HuR is increased in cancers of the breast, colon, ovary and lung and cytoplasmic immunoreactivity for HuR was found to be closely related to poor outcomes in patients with these tumors. Since the regulation of HuR function is closely linked to its subcellular localization, we evaluated, by quantitative immunohistochemistry, the impact on clinical outcome of both nuclear and cytoplasmic levels (integrated density: ID) of HuR and of nuclear/ cytoplasmic ratio (N/C) in 54 lung adenocarcinomas from stage I and II patients. Nuclear and cytoplasmic Hur IDs and N/C were not associated with age, smoking or tumor diameter. Low N/C was significantly associated with lymph-node involvement at presentation. Cox’s regression analysis showed that high cytoplasmic, but not nuclear, HuR ID and low N/C were directly associated with the risk of death and metastasis. In the multivariate analysis, low HuR N/C retained an independent negative prognostic significance relative to the risk of metastasis and death. Moreover, the levels of N/C allowed us to discriminate subjects with the highest risk of metastasis and death among patients with lung adenocarcinomas expressing high levels of cytoplasmic HuR. In conclusion, the measure of the ratio between nuclear and cytoplasmic HuR levels allows a sensitive prognostic evaluation of the clinical outcome in early stage lung adenocarcinoma patients
- PublicationOpen AccessPoly(ADP-ribose) in the skin and in melanomas(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2012) Géhl, Zsuzsanna; Bai, Péter; Bodnár, Edina; Emri, Gabriella; Remenyik, Éva; Németh, János; Gergely, Pál; Virág, László; Szabó, ÉvaCutaneous melanoma (CM) and uveal melanoma (UM) represent the most aggressive pigment cell tumor types. Our investigation examined the signaling molecule poly(ADP-ribose) (PAR) in CM and UM. We have demonstrated PAR in keratinocytes, sebocytes, hair follicles, endothelial cells and in subcutaneous adipocytes in the normal skin indicating that PAR may regulate physiological functions in these cell types. Furthermore, CM cells were PAR positive and tumor invasion level/thickness of CM correlated with the PAR content of the cell nuclei, with higher Clark and Breslow indices and AJCC scores associating with higher PAR content. This correlation was especially marked in the samples of female patients. In UM tumors (n=12) a slight overall and strong perivascular PAR staining was observed with considerable individual variations. In view of recent successful clinical trials with PARP inhibitors as adjuvant chemotherapeutic agents, our results suggest that melanomas may display differential sensitivity towards this novel therapeutic modality which should be considered for the selection of patients
- PublicationOpen AccessFAP-related desmoid tumors: a series of 44 patients evaluated in a cancer referral center(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2012) Colombo, Chiara; Foo, Wai Chin; Whiting, David; Young, Eric D.; Lusby, Kristelle; Pollock, Raphael E.; Lazar, Alexander J.; Lev, DinaDesmoid tumors (DTs), the commonest extra-intestinal manifestation of familial adenomatosis polyposis (FAP), are monoclonal neoplasms demonstrating fibroblastic - myofibroblastic differentiation; they are locally invasive without metastatic capacity. FAP-associated DT natural history knowledge is limited; we examined patient and tumor characteristics for a FAP-DT cohort and evaluated anti-DT therapy molecular target expression levels (immunohistochemical analyses, FAP-DT tissue microarray; TMA). Forty-four patients were classified as intra-abdominal (IA; n=26), abdominal wall (AW)/extra-abdominal (EA; n=12) or concomitant IA/AW (n=6) based on DT primary diagnosis location. Positive family histories were found in 62% of FAP versus 10% of DT patients. Surgery was the mainstay therapy for AW/EW patients, whereas IA DTs received surgery, chemotherapy, radiotherapy, tamoxifen, NSAIDs, and/or imatinib. Eight of 20 completely resected DTs in the IA and AW/EA groups recurred; 12 of 38 patients in these groups (33%) developed secondary lesions elsewhere. Two intestinal mesenteric DT patients died of disease, three from other cancers, 27 are alive with disease and 12 are alive without disease. All evaluable FAP-DT exhibited nuclear ß-catenin, 65% were positive for cyclin D1, and 66% expressed nuclear p53. No ERα expression was observed, but ERß was expressed in 72%. COX2 was expressed in all evaluable FAP-DTs. KIT was rarely found in DTs but both PDGFRs and their ligands were expressed. Comparing biomarker expression (IA vs. EA DTs), only nuclear ER-ß staining was significantly higher in EA lesions (p=0.0070); no other markers were site informative. Enhanced knowledge of FAP-DT molecular underpinnings will facilitate development of novel therapeutic strategies
- PublicationOpen AccessIntranasal administration: a potential solution for cross-BBB delivering neurotrophic factors(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2012) Zhu, Juehua; Jiang, Yongjun; Xu, Gelin; Liu, XinfengNeurotrophic factors (NTFs) are endogenous polypeptides that regulate the growth, survival, differentiation, and functioning of neurons. The neuroprotective effects of NTFs in experimental animals give strong rationale for developing therapies for neurological disorders. However, when NTFs are applied in clinical trials, great expectation leads to equal disappointment. NTFs are large molecular-weighted and hydrophilic proteins, which limits their access to the central nervous system (CNS) after systemic administration, principally due to poor blood-brain barrier (BBB) permeability and unfavorable pharmacokinetic profiles. Although intracerebral infusion may transport NTFs into the CNS, the invasiveness limits its clinical application. Intranasal administration has been under research for decades and presents promising outcomes in preclinical studies for brain delivering of NTFs. After intranasal delivery, NTFs gain direct and quick access into the CNS at concentrations high enough to elicit their biological effects, bypassing the BBB and minimizing systemic exposure. Due to its invasiveness and convenience, intranasal delivery is feasible for NTFs administration. Although direct evidence of nose-to-brain pathway in human is lacking due to ethical problems, the existence of the nose-to-cerebral spinal fluid pathway has been verified in men. Furthermore, there is abundant indirect evidence for the nose-to-brain pathway as determined by the efficacy of intranasally administered neuroproteins, such as insulin, oxytocin, and vasopressin in clinical trials. Based on the solid preclinical research supporting the efficacy of intranasal NTFs, and the successful clinical application of neuroproteins (not NTFs), it is time to evaluate clinical application of NTFs in treating both acute and chronic CNS diseases
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