Guido Nicolò

Bio: Guido Nicolò is an academic researcher from National Cancer Research Institute. The author has contributed to research in topics: Sentinel lymph node & Breast cancer. The author has an hindex of 29, co-authored 57 publications receiving 2813 citations. Previous affiliations of Guido Nicolò include European Institute of Oncology.

The fibronectin isoform containing the ED-B oncofetal domain: a marker of angiogenesis.

Abstract: Different fibronectin (FN) isoforms are generated by the alternative splicing of 3 regions (ED-A, ED-B and IIICS) of the primary transcript. The FN isoform containing the ED-B sequence, a complete type-III-homology repeat, while having extremely restricted distribution in normal adult tissues, reveals high expression in fetal and tumor tissues. Using the monoclonal antibody (MAb) BC-I, specific for the FN isoform containing the ED-B sequence (B+.FN), we demonstrated here, using immunohistochemical techniques, that while this FN isoform is undetectable in mature vessels, it is highly expressed during angiogenesis both in neoplastic and in normal tissues, as in the case of the functional layer of endometrium during the proliferative phase. B+.FN is thus a marker for the formation of new vessels, and the BC-I MAb may be a useful reagent for evaluating the level of the angiogenetic process in different neoplasms.

Structure of the Supernumerary Ring and Giant Rod Chromosomes in Adipose Tissue Tumors

Abstract: Supernumerary ring or giant rod marker chromosomes are a characteristic of well-differentiated liposarcomas (WDLPS) and atypical lipomas (ALP) and are often observed as the sole cytogenetic abnormality, but are rare in lipomas. Using a combination of different methods, we extensively investigated the structure and composition of rings and giant rods in a series of 17 WDLPS-ALP samples and three intra- or intermuscular lipomas (IMLP), revealing a unique combination of particular features strikingly related to these tumors. Although the rings and rods displayed in vitro and in vivo stability, the presence of alpha-satellites could not be detected on these supernumerary structures. Comparative genomic hybridization analysis, in combination with fluorescence in situ hybridization, identified the chromosomal regions contributing to the formation of these chromosomes: in WDLPS-ALP, all carried amplifications of 12q 14-15 and the MDM2 gene, with variable other noncontiguous regions. In the three IMLP, the rings consistently carried amplifications of 12q15-21 and 1q21, but increased copies of MDM2 were found in only one case. Other genes located more proximal in 12q14-15 were amplified in several WDLPS-ALP, but showed a normal copy number in IMLP. Furthermore, the immunohistochemical expression of the MDM2 protein was detected in most (12/14) WDLPS-ALP, in 1-30% of the cells, but never in IMLP. These supernumerary chromosomes represent a peculiar kind of amplification structure, midway between double minute chromosomes and homogeneously staining regions, but the mechanisms underlying the formation of these structures remain obscure.

Expression of different tenascin isoforms in normal, hyperplastic and neoplastic human breast tissues.

Abstract: Functionally different tenascin (TN) isoforms, containing varying numbers of a 91 amino-acid motif resembling the fibronectin type-III homology repeat, may be generated by alternative splicing of the TN primary transcript. In fact, only the TN isoform containing the alternatively spliced region can induce loss of focal adhesion in cultured cells and seems to be able to facilitate cell migration. We examined the patterns of alternative splicing of the TN primary transcript in normal, hyperplastic and neoplastic breast tissues, and found that, in all the invasive breast carcinomas analyzed, the relative amount of TN mRNA in which the alternatively spliced region was included was about 10 times higher than in RNA from normal breast tissues. A similar result was observed in phyllodes tumors and in those fibroadenomas which showed very high stromal cellularity. Western-blot analysis using different monoclonal antibodies showed the same pattern as that seen in Northern blotting. The data reported here suggest that, in the breast, expression of the high-molecular-mass TN isoform is a marker of stromal element proliferation and that, in invasive breast carcinomas, this TN isoform could play a role in generating a permissive environment for proliferation, invasion and metastasis of neoplastic epithelial cells.

Complex composition and co-amplification of SAS and MDM2 in ring and giant rod marker chromosomes in well-differentiated liposarcoma.

Abstract: Extra abnormal chromosomes (rings and giant rods) containing chromosome 12 sequences are characteristic of well-differentiated liposarcoma (WDLPS). By whole chromosome painting we found in 6 WDLPS that minimally 5 chromosomes had contributed to the formation of the extra abnormal chromosomes. To the constant chromosome 12 contribution, sequences were variably added from chromosomes 1, 4, and 16. Material from chromosomes 1, 4, and 12 was identified by painting in interphase nuclear projections ("blebs") and in micronuclei consistent with the concept that blebs are precursors to micronuclei. The complexity of the mechanisms generating the extra abnormal chromosomes in WDLPS was also attested to by the diversity and, in some cases, intricacy of the patterns of fluorescence. To begin to fathom the function of the extra abnormal chromosomes we examined the amplification of genes, including SAS, MDM2, and GADD153/CHOP, known to be in the region 12q13-14. SAS and MDM2 demonstrated constant co-amplification. GADD153/CHOP, which is critically rearranged in myxoid liposarcoma, was not amplified in WDLPS.

Interfering with pH regulation in tumours as a therapeutic strategy

Abstract: The high metabolic rate of tumours often leads to acidosis and hypoxia in poorly perfused regions. Tumour cells have thus evolved the ability to function in a more acidic environment than normal cells. Key pH regulators in tumour cells include: isoforms 2, 9 and 12 of carbonic anhydrase, isoforms of anion exchangers, Na+/HCO3- co-transporters, Na+/H+ exchangers, monocarboxylate transporters and the vacuolar ATPase. Both small molecules and antibodies targeting these pH regulators are currently at various stages of clinical development. These antitumour mechanisms are not exploited by the classical cancer drugs and therefore represent a new anticancer drug discovery strategy.

Regulating the p53 pathway: in vitro hypotheses, in vivo veritas

Abstract: Mutations in TP53, the gene that encodes the tumour suppressor p53, are found in 50% of human cancers, and increased levels of its negative regulators MDM2 and MDM4 (also known as MDMX) downregulate p53 function in many of the rest. Understanding p53 regulation remains a crucial goal to design broadly applicable anticancer strategies based on this pathway. This Review of in vitro studies, human tumour data and recent mouse models shows that p53 post-translational modifications have modulatory roles, and MDM2 and MDM4 have more profound roles for regulating p53. Importantly, MDM4 emerges as an independent target for drug development, as its inactivation is crucial for full p53 activation.

Lymphatic mapping and sentinel lymphadenectomy for breast cancer

Abstract: Lymphatic mapping and sentinel lymphadenectomy has become an important tool for axillary lymph node staging in women with early-stage breast cancer. This review examines data regarding the staging accuracy, indications and technical aspects of the procedure, and clinical trials investigating the technique. Multiple studies now confirm that sentinel lymphadenectomy accurately stages the axilla and is associated with less morbidity than axillary dissection. Blue dye, radiocolloid, or both can be used to identify the sentinel node, and several injection techniques may be used successfully. Many patient factors previously thought to affect accuracy of the procedure have now been shown to be of limited significance. The indications for the procedure are expanding, and the histopathologic evaluation of the sentinel node and the role of lymphoscintigraphy have been clarified. Clinical trials are now underway that will determine the prognostic significance of micrometastases and the therapeutic benefit of axillary dissection in women with and without sentinel node metastases. Incorporation of sentinel lymphadenectomy into routine clinical practice will maintain accurate axillary staging with lower morbidity and improved quality of life for women with early-stage breast cancer.

Assessing the significance of chromosomal aberrations in cancer: Methodology and application to glioma

Abstract: Comprehensive knowledge of the genomic alterations that underlie cancer is a critical foundation for diagnostics, prognostics, and targeted therapeutics. Systematic efforts to analyze cancer genomes are underway, but the analysis is hampered by the lack of a statistical framework to distinguish meaningful events from random background aberrations. Here we describe a systematic method, called Genomic Identification of Significant Targets in Cancer (GISTIC), designed for analyzing chromosomal aberrations in cancer. We use it to study chromosomal aberrations in 141 gliomas and compare the results with two prior studies. Traditional methods highlight hundreds of altered regions with little concordance between studies. The new approach reveals a highly concordant picture involving ≈35 significant events, including 16–18 broad events near chromosome-arm size and 16–21 focal events. Approximately half of these events correspond to known cancer-related genes, only some of which have been previously tied to glioma. We also show that superimposed broad and focal events may have different biological consequences. Specifically, gliomas with broad amplification of chromosome 7 have properties different from those with overlapping focalEGFR amplification: the broad events act in part through effects on MET and its ligand HGF and correlate with MET dependence in vitro. Our results support the feasibility and utility of systematic characterization of the cancer genome.