Biomedical subjects

Laura Casorzo

Publications and source records attributed to Laura Casorzo.

8 recordsLinked to original sources

PubMed2021

ERBB3 overexpression due to miR-205 inactivation confers sensitivity to FGF, metabolic activation, and liability to ERBB3 targeting in glioblastoma.

In glioblastoma (GBM), the most frequent and lethal brain tumor, therapies suppressing recurrently altered signaling pathways failed to extend survival. However, in patient subsets, specific genetic lesions can confer sensitivity to targeted agents. By exploiting an integrated model based on patient-derived stem-like cells, faithfully recapitulating the original GBMs in vitro and in vivo, here, we identify a human GBM subset (∼9% of all GBMs) characterized by ERBB3 overexpression and nuclear accumulation. ERBB3 overexpression is driven by inheritable promoter methylation or post-transcriptional silencing of the oncosuppressor miR-205 and sustains the malignant phenotype. Overexpressed ERBB3 behaves as a specific signaling platform for fibroblast growth factor receptor (FGFR), driving PI3K/AKT/mTOR pathway hyperactivation, and overall metabolic upregulation. As a result, ERBB3 inhibition by specific antibodies is lethal for GBM stem-like cells and xenotransplants. These findings highlight a subset of patients eligible for ERBB3-targeted therapy.

Antibodies↗

PubMed2005

Fluorescence in situ hybridization (FISH) evaluation of chromosomes 6, 7, 9 and 10 throughout human melanocytic tumorigenesis.

Loss of the 9p21 region, 6q and 10q and gain of chromosome 7 are the most frequent chromosomal abnormalities found in human melanomas, but very few cytogenetic data are available regarding dysplastic and common naevi. To study the occurrence of the most consistent chromosomal changes during melanocytic tumorigenesis, archival samples from 30 common naevi and 30 naevus-associated melanomas were analysed by interphase fluorescence in situ hybridization (FISH) using centromeric probes for chromosomes 9 and 7 and locus-specific probes for 9p21, 6q11.1, 6q24.1, 10p15.3 and 10q23.1 regions. In naevus-associated melanomas, separate evaluations were made for sectors corresponding to residual naevus, dysplastic naevus, radial growth phase melanoma and vertical growth phase melanoma. No chromosomal aberrations were found in common naevi, but monosomy 7 was observed in one case. In naevus-associated melanomas, loss of the entire chromosome 9 or of the 9p21 region was observed in 56% of common and 54% of dysplastic naevus sectors, in 64% of radial growth phase melanoma and in 82% of vertical growth phase melanoma. Loss of the long arm of chromosome 6, monosomy 10 and deletion 10q were exclusively confined to radial (18% for both chromosomes) and vertical (29 and 59%, respectively) growth phase melanomas. Polysomy of chromosome 7 was detected only in melanoma sectors (radial growth phase, 14%; vertical growth phase, 59%). The high incidence of 9p21 loss in melanoma-associated naevi, which is maintained in all evolutionary phases of melanocytic tumorigenesis, and the complete absence of chromosomal aberrations in common naevi, strongly suggest that 9p21 loss may be regarded as a cytogenetic marker of melanocytic naevi with a high potential for progression.

Chromosome Aberrations↗

PubMed2005

HER2 gene-amplified breast cancers with monosomy of chromosome 17 are poorly responsive to trastuzumab-based treatment.

Although HER2 gene status determines the eligibility of breast cancer patients to trastuzumab therapy, only a fraction of HER2 gene-amplified cancers are actually responsive, indicating that complex genotypical profiles might sustain HER2-targeted therapy responsiveness. To identify genetic factors modulating the response to HER2-targeted therapy, the numerical status of chromosome 17 was evaluated in HER2 gene-amplified tumor specimens from 43 patients who received trastuzumab-based treatment for advanced breast cancer, and in 60 unamplified breast carcinomas. Archival tumor specimens were analyzed by interphase fluorescence in situ hybridization (FISH) using a centromeric probe for chromosome 17 simultaneously with the HER2/neu human gene-specific probe. In the 43 patients who received trastuzumab-based treatment, response rate and time to progression (TTP) were compared between subgroups according to chromosome 17 status. Numerical aberrations of chromosome 17 were found in 65% of HER2-amplified tumors (single centromeric signal, 44%; >3 centromeric signals, 21%) and 60% of unamplified cancers (single centromeric signal, 43%; >3 centromeric, 17%). In the 43 treated metastatic breast cancer patients, trastuzumab was combined with docetaxel (35 patients), paclitaxel (2 patients), or vinorelbine (6 patients). Response rate was 92% in patients with >2 centromeric signals (chromosome 17 eusomy/polysomy), and 53% in patients whose tumor showed a single signal (chromosome 17 monosomy) (p=0.005). Chromosome 17 numerical status was not found to affect TTP. Multivariate logistic regression analysis confirmed that the effect of chromosome 17 monosomy on tumor response was independent of other potential clinical variables. Our findings suggest that 17 monosomy defines a subgroup of HER2 gene-amplified breast cancer characterized by reduced responsiveness to trastuzumab-based treatment. Further studies on the imbalance between the amplified HER2 gene and functionally antagonist gene(s) on chromosome 17 are warranted.

Adult↗

PubMed2004

Leukemia-derived immature dendritic cells differentiate into functionally competent mature dendritic cells that efficiently stimulate T cell responses.

Primary acute myeloid leukemia cells can be induced to differentiate into dendritic cells (DC). In the presence of GM-CSF, TNF-alpha, and/or IL-4, leukemia-derived DC are obtained that display features of immature DC (i-DC). The aim of this study was to determine whether i-DC of leukemic origin could be further differentiated into mature DC (m-DC) and to evaluate the possibility that leukemic m-DC could be effective in vivo as a tumor vaccine. Using CD40L as maturating agent, we show that leukemic i-DC can differentiate into cells that fulfill the phenotypic criteria of m-DC and, compared with normal counterparts, are functionally competent in vitro in terms of: 1) production of cytokines that support T cell activation and proliferation and drive Th1 polarization; 2) generation of autologous CD8(+) CTLs and CD4(+) T cells that are MHC-restricted and leukemia-specific; 3) migration from tissues to lymph nodes; 4) amplification of Ag presentation by monocyte attraction; 5) attraction of naive/resting and activated T cells. Irradiation of leukemic i-DC after CD40L stimulation did not affect their differentiating and functional capacity. Our data indicate that acute myeloid leukemia cells can fully differentiate into functionally competent m-DC and lay the ground for testing their efficacy as a tumor vaccine.

CD40 Ligand↗

PubMed2004

HER2 and central nervous system metastasis in patients with breast cancer.

We report a case of a patient who developed a central nervous system (CNS) metastasis 17 months after surgery and adjuvant therapy for stage II breast cancer. The HER2 status of the primary tumor as determined by immunohistochemistry (IHC) was 1+, and fluorescence in situ hybridization (FISH) performed retrospectively showed a borderline-negative result (ratio, 1:9), although HER2 amplification was present in a minority of breast cancer cells. By contrast, the HER2 status of the CNS metastasis was positive by IHC (3+) and FISH (ratio, 3:7). This report discusses the possibility that, for metastatic invasion into the CNS, clonal selection may occur, favoring HER2-positive cell clones.

Breast Neoplasms↗

PubMed2003

Cytogenetic findings in a case of dedifferentiated chondrosarcoma.

Cytogenetic analysis of a case of dedifferentiated chondrosarcoma with a malignant fibrous histiocytoma (MFH) component revealed a near-triploid karyotype with multiple copies of chromosome 7, deletion of chromosome arm 9p, and a derivative chromosome 19 [add(19p)] in each metaphase. Whereas numerical anomalies of chromosome 7 have been frequently reported in chondrosarcoma, deletion 9p and add (19p) have been observed in MFH. A putative MFH tumor suppressor gene could be present in a critical region on chromosome bands 9p21~p22.

Aged↗

PubMed2003

Deletions of 17p are associated with transition from early to advanced colorectal cancer.

Several chromosome defects parallel morphologic evolution in colorectal tumor progression. Allelic losses in the short arm of chromosome 17, the majority encompassing the 17p13.3 band, have been found in advanced cancer in the absence of TP53 mutations, suggesting that loss of genes in this chromosome region is relevant for tumorigenesis. The aim of this study was to investigate 17p13.3 deletions throughout the colorectal tumor progression using two-color fluorescence in situ hybridization. Histologic sections from 20 colorectal adenomas containing early invasive carcinoma were analyzed by interphase fluorescence in situ hybridization using a centromeric probe for chromosome 17 simultaneously with a subtelomeric probe mapping to the 17p13.3 band. Separate evaluation was made for sectors corresponding to adenoma tissue with low-grade dysplasia, high-grade dysplasia, and early cancer. The same technique was also used in 20 cases of advanced adenocarcinoma of the large bowel. Loss of one centromeric signal was observed in 20, 40, 50, and 10% of low-grade dysplasia, high-grade dysplasia, early cancer, and advanced cancer, respectively (P<0.02 early vs. advanced cancer). Subtelomeric 17p deletions were seen in 60% of advanced cancer and in 15% of early cancer (P<0.01). These findings indicate that loss of genes from the 17p13.3 chromosome region may play an important role in sustaining the transition from early to advanced cancer in colorectal tumor progression.

Adenocarcinoma↗

PubMed2003

HER2 testing in gastric cancer: molecular morphology and storage time-related changes in archival samples.

Seventy-two archival specimens of advanced gastric adenocarcinoma were analyzed by fluorescence in situ hybridization and immunohistochemistry for HER2 gene status. Gene amplification and concomitant protein overexpression were detected in 15.2% of cases. Intratumor topographical variability of HER2 amplification was observed, indicative of the late involvement of HER gene in gastric tumorigenesis. No significant correlations were found between HER2 status and histopathologic type, grade of differentiation, and Goseki classification of carcinomas, suggesting that HER2 gene is variably linked with the morphogenesis of gastric adenocarcinoma. A significant decrease of the incidence of HER2 amplified carcinomas in function of the duration of the storage of paraffin blocks was observed: 42-33% for tumor specimens paraffin-embedded in 2002-2001; 8.3%, 15.7%, 11.1% for the years 2000, 1999, 1998, respectively; 0% for cases embedded during 1997. According to these results, the reliability of the FISH and immunohistochemical assays decreases after prolonged storage of paraffin-embedded specimens.

Adenocarcinoma↗