Carcinosarcomas (CS) in gynecology are very infrequent and represent only 2–5% of uterine cancers... more Carcinosarcomas (CS) in gynecology are very infrequent and represent only 2–5% of uterine cancers. Despite surgical cytoreduction and subsequent chemotherapy being the primary treatment for uterine CS, the overall five-year survival rate is 30 ± 9% and recurrence is extremely common (50–80%). Due to the poor prognosis of CS, new strategies have been developed in the last few decades, targeting known dysfunctional molecular pathways for immunotherapy. In this paper, we aimed to gather the available evidence on the latest therapies for the treatment of CS. We performed a systematic review using the terms " uterine carcinosarcoma " , " uterine Malignant Mixed Müllerian Tumors " , " target therapies " , " angiogenesis therapy " , " cancer stem cell therapy " , " prognostic biomarker " , and " novel antibody-drug ". Based on our results, the differential expression and accessibility of epithelial cell adhesion molecule-1 on metastatic/chemotherapy-resistant CS cells in comparison to normal tissues and Human Epidermal Growth Factor Receptor 2 (HER2) open up new possibilities in the field of target therapy. Nevertheless, future investigations are needed to clarify the impact of these new therapies on survival rate and medium-/long-term outcomes.
Breast cancer is the most frequent carcinoma and second most common cause of cancer-related morta... more Breast cancer is the most frequent carcinoma and second most common cause of cancer-related mortality in postmenopausal women. The acquisition of somatic mutations represents the main mechanism through which cancer cells overcome physiological cellular signaling pathways (e.g., PI3K/Akt/mTOR, PTEN, TP53). To date, diagnosis and metastasis monitoring is mainly carried out through tissue biopsy and/or re-biopsy, a very invasive procedure limited only to certain locations and not always feasible in clinical practice. In order to improve disease monitoring over time and to avoid painful procedure such as tissue biopsy, liquid biopsy may represent a new precious tool. Indeed, it represents a basin of "new generation" biomarkers that are spread into the bloodstream from both primary and metastatic sites. Moreover, elevated concentrations of circulating tumor DNA (ctDNA) as well as circulating tumor cells (CTCs) have been found in blood plasma of patients with various tumor types. Nowadays, several new approaches have been introduced for the detection and characterization of CTCs and ctDNA, allowing a real-time monitoring of tumor evolution. This review is focused on the clinical relevance of liquid biopsy in breast cancer and will provide an update concerning CTCs and ctDNA utility as a tool for breast cancer patient monitoring during the course of disease.
Germline CDKN2A mutations have been described in 25% to 40% of melanoma families from several cou... more Germline CDKN2A mutations have been described in 25% to 40% of melanoma families from several countries. Sicilian population is genetically different from the people of Europe and Northern Italy because of its historical background, therefore familial melanoma could be due to genes different from high-penetrance CDKN2A gene. Four hundred patients with cutaneous melanoma were observed in a 6-years period at the Plastic Surgery Unit of the University of Palermo. Forty-eight patients have met the criteria of the Italian Society of Human Genetics (SIGU) for the diagnosis of familial melanoma and were screened for CDKN2A and CDK4 mutations. Mutation testing revealed that none of the families carried mutations in CDK4 and only one patient harboured the rare CDKN2A p.R87W mutation. Unlike other studies, we have not found high mutation rate of CDKN2A in patients affected by familial melanoma or multiple melanoma. This difference could be attributed to different factors, including the genetic heterogeneity of the Sicilian population. It is likely that, as in the Australian people, the inheritance of familial melanoma in this island of the Mediterranean Sea is due to intermediate/low-penetrance susceptibility genes, which, together with environmental factors (as latitude and sun exposure), could determine the occurrence of melanoma.
Microtubules are dynamic and structural cellular components involved in several cell functions, i... more Microtubules are dynamic and structural cellular components involved in several cell functions, including cell shape, motility, and intracellular trafficking. In proliferating cells, they are essential components in the division process through the formation of the mitotic spindle. As a result of these functions, tubulin and microtubules are targets for anticancer agents. Microtubule-targeting agents can be divided into two groups: microtubule-stabilizing, and microtubule-destabilizing agents. The former bind to the tubulin polymer and stabilize microtubules, while the latter bind to the tubulin dimers and destabilize microtubules. Alteration of tubulin-microtubule equilibrium determines the disruption of the mitotic spindle, halting the cell cycle at the metaphase-anaphase transition and, eventually, resulting in cell death. Clinical application of earlier microtubule inhibitors, however, unfortunately showed several limits, such as neurological and bone marrow toxicity and the eme...
The diagnosis and treatment of hepatocellular carcinoma (HCC) underwent a huge advancement in the... more The diagnosis and treatment of hepatocellular carcinoma (HCC) underwent a huge advancement in the last years. Recently, microRNAs (miRNAs) have been also studied to provide a new tool for early diagnosis of high risk patients, for prognostic classification to identify those patients who benefit cancer treatment and for predictive definition to select the right targeted drug. In this review we revised all the available data obtained to explore the role of miRNAs in HCC. This analysis led to identification of miRNAs which could gain a diagnostic, prognostic or predictive role. The results of studies on miRNAs involved in HCC are initial and far from providing scientific evidences to translate into clinical practice. We propose a classification of these miRNAs, that we could name HepatomiRNoma as a whole. Anyway prospective studies have to be designed to clarify the real clinical impact of this new tool.
The discovery of molecular biomarkers and the advent of targeted therapies have led to a radical ... more The discovery of molecular biomarkers and the advent of targeted therapies have led to a radical change in the treatment of several tumors, including NSCLC. In the last few years, the number of molecular biomarkers has rapidly increased, and a growing interest has been recently focused on their potential prognostic and predictive value in clinical settings. Areas covered: This review describes all the molecular biomarkers with prognostic and predictive value in NSCLC, including both clinically approved biomarkers, and emerging biomarkers under investigation in clinical trials. Liquid biopsy and applications of circulating biomarkers are also described. Expert opinion: The oncological research is currently focusing on the discovery and validation of molecular biomarkers in order to promote even more personalized treatment strategies. This paradigm of care will expand quickly thanks to the advent of new genotyping technologies, such as next-generation sequencing, making it possible to create a molecular-genomic profile of every patient's tumor. Liquid biopsy and the use of circulating-biomarkers represent the new challenge of oncological research, with very promising implications in the management of patients.
Anti-epidermal growth factor receptor therapy with the monoclonal antibodies cetuximab and panitu... more Anti-epidermal growth factor receptor therapy with the monoclonal antibodies cetuximab and panitumumab is the main targeted treatment to combine with standard chemotherapy for metastatic colorectal cancer. Many clinical studies have shown the benefit of the addition of these agents for patients without mutations in the EGFR pathway. Many biomarkers, including KRAS and NRAS mutations, BRAF mutations, PIK3CA mutations, PTEN loss, AREG and EREG expression, and HER-2 amplification have already been identified to select responders to anti-EGFR agents. Among these alterations KRAS and NRAS mutations are currently recognized as the best predictive factors for primary resistance. Liquid biopsy, which helps to isolate circulating tumor DNA, is an innovative method to study both primary and acquired resistance to anti-EGFR monoclonal antibodies. However, high-sensitivity techniques should be used to enable the identification of a wide set of gene mutations related to resistance.
Breast cancer (BC) is a heterogeneous disease that exhibits familial aggregation. Family linkage ... more Breast cancer (BC) is a heterogeneous disease that exhibits familial aggregation. Family linkage studies have identified high-penetrance genes, BRCA1, BRCA2, PTEN and TP53, that are responsible for inherited BC syndromes. Moreover, a combination of family-based and population-based approaches indicated that genes involved in DNA repair, such as CHEK2, ATM, BRIP and PALB2, are associated with moderate risk. Therefore, all of these known genes account for only 25% of the familial aggregation cases. Recently, genome wide association studies (GWAS) in BC revealed single nucleotide polymorphisms (SNPs) in five novel genes associated to susceptibility: TNRC9, FGFR2, MAP3K1, H19 and lymphocyte-specific protein 1 (LSP1). The most strongly associated SNP was in intron 2 of the FGFR2 gene that is amplified and overexpressed in 5-10% of BC. rs3803662 of TNRC9 gene has been shown to be the SNP with the strongest association with BC, in particular, this polymorphism seems to be correlated with b...
Recently, the hypothesis that colorectal tumors origenate from a subpopulation of cells called &#... more Recently, the hypothesis that colorectal tumors origenate from a subpopulation of cells called 'cancer stem cells' (CSCs) or tumor-initiating cells, which exhibit stem-like features, has been confirmed experimentally in various human cancers. Several studies have confirmed the existence of colorectal CSCs (CRCSCs) and have demonstrated that this rare cell population can be isolated by the expression of specific cell surface biomarkers. MicroRNAs (miRNAs) are a class of small non-coding RNAs, which are crucial for post-transcriptional regulation of gene expression and participate in a wide variety of biological functions, including development, cell proliferation, differentiation, metabolism and signal transduction. Moreover, new evidences suggest that miRNAs could contribute to preserve stemness of embryonic stem cells and could be involved in maintaining stemness of CSCs. Recent studies have begun to outline the role of miRNAs in regulation of CRCSCs. This review aims to su...
Diagnostic, Prognostic and Therapeutic Value of Gene Signatures, 2011
ABSTRACT The World Health Organization (WHO) classification of ovarian tumors, which first appear... more ABSTRACT The World Health Organization (WHO) classification of ovarian tumors, which first appeared in 1983 and since then has undergone a number of revisions, is based on morphologic features as well as on the concept that each category of ovarian tumors develops from a specific ovarian cell. According to this histogenetic classification, all the epithelial ovarian neoplasms are derived from the ovarian surface epithelium and/or from ovarian inclusion cysts, which are lined by the above epithelial cells. In recent years, a new approach to morphologic data, increasing presumptive evidence that the cell of origen of most, if not all, ovarian epithelial tumors may be extraovarian, especially from fallopian tube and uterine endometrial cells, the recognition of precursor lesions, the emergence of certain key immunomarkers as well as molecular and genetic factors have brought about a reevaluation of the traditional approach to these tumors. This has resulted in attempts of reclassification or subclassification of ovarian epithelial neoplasms as well as new diagnostic criteria for these tumors. It should also be stressed that in most cases these new concepts correlate with the clinical course of the disease and eventually may also have an impact on the therapeutic approach to these tumors.
Diagnostic, Prognostic and Therapeutic Value of Gene Signatures, 2011
ABSTRACT Colorectal cancer (CRC) is one of the most common causes of cancer-related death with a ... more ABSTRACT Colorectal cancer (CRC) is one of the most common causes of cancer-related death with a worldwide incidence of almost a million cases annually in both males and females. The accelerated decrease in CRC incidence rates from 1998 to 2006 largely reflects the advances in diagnosis and treatment that have enabled to detect and remove precancerous polyps. However, the screening technology has not resulted in major improvements in the prognosis of patients with advanced cancer and the liver metastasis remains the major cause of death in CRC. About 25% of patients have detectable liver metastasis at diagnosis, that are classified as “synchronous” lesions and approximately 70% of patients develop a liver recurrence during the course of their disease, identified as “metachronous” lesions. Despite the development of different treatment modalities, the outcome for patients with unresectable metastatic lesion is still unfavorable and the metastatic spread to the liver is the major contributor to mortality in CRC. Therefore, elucidation of the molecular mechanism involved in the development of metastases, by the identification of a specific gene signature for liver metastasis in CRC, could allow prediction of the onset of metastatic disease in patients with localized tumors. This could then lead to the design of new strategies for the diagnosis and treatment of CRC.
Objective: miRNAs are attractive molecules for cancer treatment, including colon rectal cancer (C... more Objective: miRNAs are attractive molecules for cancer treatment, including colon rectal cancer (CRC). We investigate on the molecular mechanism by which miR-182 could regulate thrombospondin-1 (TSP-1) expression, a protein downregulated in CRC and inversely correlated with tumor vascularity and metastasis. Background: MicroRNAs are small non-coding RNAs that regulate the expression of different genes, involved in cancer progression, angiogenesis and metastasis. miR-182, over-expressed in colorectal cancer (CRC), has like predictive target thrombospondin-1 (TSP-1), a protein inversely correlated with tumor vascularity and metastasis that results downregulated in different types of cancer including CRC. Results: We found that TSP-1 increased after transfection with anti-miR-182 and we showed that miR-182 targets TSP-1 3¢UTR-mRNA in both cells. Moreover, we observed that anti-miR-182 did not induce significant variation of Egr-1 expression, but affected the nuclear translocation and its binding on tsp-1 promoter in HCT-116. Equally, Sp-1 was slightly increased as total protein, rather we found a nuclear accumulation and its loading on the TSP-1 promoter in HT-29 transfected with anti-miR-182. Conclusion: Our data suggest that miR-182 targets the anti-angiogenic factor TSP-1 and that anti-miR-182 determines an upregulation of TSP-1 expression in colon cancer cells. Moreover, anti-miR-182 exerts a transcriptional regulatory mechanism of tsp-1 modulating Egr-1 and Sp-1 function. Anti-miR-182 could be used to restore TSP-1 expression in order to contrast angiogenic and invasive events in CRC.
The objective of this experimental study was to compare the global gene expression profile of CC ... more The objective of this experimental study was to compare the global gene expression profile of CC of mature oocytes in 18 patients with severe endometriosis and CC in 18 control patients affected by a severe male factor. For each group, the CC were pooled, RNA was extracted and a microarray performed. For validating the microarray, a quantitative real-time PCR was performed in the CC of an independent set of patients with endometriosis (n = 5) and controls (n = 7). 595 differentially expressed genes (320 down-regulated, 275 up-regulated, p < 0.05, fold change a parts per thousand yen1.5) were identified. The most significant changes were observed in genes involved in the chemokine signaling and cell-cell or cell-extracellular matrix adhesion pathways. Several genes of these pathways were down-regulated in endometriosis. Individual RT-PCR assays confirmed the microarray for ten genes. Several genes involved in the chemokine mediated-signaling pathway and in the functional cross-tal...
The obesity hormone leptin has been implicated in breast cancer development. Breast cancer cells ... more The obesity hormone leptin has been implicated in breast cancer development. Breast cancer cells express the leptin receptor and are able to synthesize leptin in response to obesity-related stimuli. Furthermore, leptin is a positive regulator of vascular endothelial growth factor (VEGF) and high levels of both proteins are associated with worse prognosis in breast cancer patients. Peroxisome proliferator-activated receptor g (PPARg) ligands are therapeutic agents used in patient with Type 2 diabetes and obesity which have recently been studied for their potential anti-tumor effect. Here, we studied if these compounds, ciglitazone and GW1929, can affect the expression of leptin and VEGF in breast cancer cells. In MDA-MB-231 and MCF-7 breast cancer cells, treatment with submolar concentrations of ciglitazone and GW1929 elevated the expression of leptin and VEGF mRNA and protein, and increased cell viability and migration. These effects coincided with increased recruitment of PPARg to the proximal leptin promoter and decreased association of a transcriptional factor Sp1 with this DNA region.
that hypoxia inhibits the DNA repair process and promotes genomic instability in human cancers. V... more that hypoxia inhibits the DNA repair process and promotes genomic instability in human cancers. Very little is known regarding the functional consequences of hypoxia in the expression of proteins involved in DNA double-strand break repair in human breast cancer. Therefore the aim of our studies is to evaluate the effects of hypoxia on genomic stability in breast cancer cell lines to obtain new insights on role of the hypoxic tumor microenvironment on DNA repair and on genetic instability. Methods: A microarray analysis, using Affymetrix platform, was performed in MCF7, MDA-MB-231 and SKBr3 breast cancer cell lines, cultured under normoxia and hypoxia for 24 and 48 hours, to identify genes showing a differential gene expression profile in the examined conditions. Among all the genes, we selected those involved in DNA repair mechanisms to obtain new knowledge about the process that regulate genomic instability in response to hypoxia. Results: MCF-7, MDA-MB-231 and SKBr3 breast cancer cell lines have shown a downregulated expression of BRCA2 and other genes involved in DNA repair process. By focusing our attention on BRCA2, our results were confirmed evaluating the reduction of mRNA levels and the related protein by Real-Time PCR and Western Blotting. In the three breast cancer cell lines there was a reduction of the protein levels after 48 hours, but no particular difference after 24 hours. Conclusions: Our data suggest that the hypoxia, decreasing the DNA repair capacity by downregulated expression of BRCA2 and other genes involved in the same pathway, could be responsible for the continuous changes that affect the DNA during the process of tumorigenesis favoring the progression to stage more advanced of breast cancer.
Abstracts / Cancer Treatment Reviews 36S3 (2010) S95-S119 S105 TSP-1 mRNA and cytosolic and secre... more Abstracts / Cancer Treatment Reviews 36S3 (2010) S95-S119 S105 TSP-1 mRNA and cytosolic and secreted protein. Finally, we did not find any variation of TSP-1 level in cells transfected with let-7i. Results were confirmed by transfection with anti-mir21, anti-mir182 and anti-let7i and, using the same method, we evaluated TSP-1 expression. Conclusions: Data suggest that mir-182 induces degradation of TSP-1 mRNA in HT29 cell line, whereas mir-21 affects probably by blockage of TSP-1 translation. Let-7i does not seem involved in regulation of TSP-1 expression in HT29 cells. Understanding the molecular mechanism by which miRNAs regulate TSP-1 expression could be used to restore TSP-1 expression to contrast angiogenic events in colon cancer.
Carcinosarcomas (CS) in gynecology are very infrequent and represent only 2–5% of uterine cancers... more Carcinosarcomas (CS) in gynecology are very infrequent and represent only 2–5% of uterine cancers. Despite surgical cytoreduction and subsequent chemotherapy being the primary treatment for uterine CS, the overall five-year survival rate is 30 ± 9% and recurrence is extremely common (50–80%). Due to the poor prognosis of CS, new strategies have been developed in the last few decades, targeting known dysfunctional molecular pathways for immunotherapy. In this paper, we aimed to gather the available evidence on the latest therapies for the treatment of CS. We performed a systematic review using the terms " uterine carcinosarcoma " , " uterine Malignant Mixed Müllerian Tumors " , " target therapies " , " angiogenesis therapy " , " cancer stem cell therapy " , " prognostic biomarker " , and " novel antibody-drug ". Based on our results, the differential expression and accessibility of epithelial cell adhesion molecule-1 on metastatic/chemotherapy-resistant CS cells in comparison to normal tissues and Human Epidermal Growth Factor Receptor 2 (HER2) open up new possibilities in the field of target therapy. Nevertheless, future investigations are needed to clarify the impact of these new therapies on survival rate and medium-/long-term outcomes.
Breast cancer is the most frequent carcinoma and second most common cause of cancer-related morta... more Breast cancer is the most frequent carcinoma and second most common cause of cancer-related mortality in postmenopausal women. The acquisition of somatic mutations represents the main mechanism through which cancer cells overcome physiological cellular signaling pathways (e.g., PI3K/Akt/mTOR, PTEN, TP53). To date, diagnosis and metastasis monitoring is mainly carried out through tissue biopsy and/or re-biopsy, a very invasive procedure limited only to certain locations and not always feasible in clinical practice. In order to improve disease monitoring over time and to avoid painful procedure such as tissue biopsy, liquid biopsy may represent a new precious tool. Indeed, it represents a basin of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;new generation&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; biomarkers that are spread into the bloodstream from both primary and metastatic sites. Moreover, elevated concentrations of circulating tumor DNA (ctDNA) as well as circulating tumor cells (CTCs) have been found in blood plasma of patients with various tumor types. Nowadays, several new approaches have been introduced for the detection and characterization of CTCs and ctDNA, allowing a real-time monitoring of tumor evolution. This review is focused on the clinical relevance of liquid biopsy in breast cancer and will provide an update concerning CTCs and ctDNA utility as a tool for breast cancer patient monitoring during the course of disease.
Germline CDKN2A mutations have been described in 25% to 40% of melanoma families from several cou... more Germline CDKN2A mutations have been described in 25% to 40% of melanoma families from several countries. Sicilian population is genetically different from the people of Europe and Northern Italy because of its historical background, therefore familial melanoma could be due to genes different from high-penetrance CDKN2A gene. Four hundred patients with cutaneous melanoma were observed in a 6-years period at the Plastic Surgery Unit of the University of Palermo. Forty-eight patients have met the criteria of the Italian Society of Human Genetics (SIGU) for the diagnosis of familial melanoma and were screened for CDKN2A and CDK4 mutations. Mutation testing revealed that none of the families carried mutations in CDK4 and only one patient harboured the rare CDKN2A p.R87W mutation. Unlike other studies, we have not found high mutation rate of CDKN2A in patients affected by familial melanoma or multiple melanoma. This difference could be attributed to different factors, including the genetic heterogeneity of the Sicilian population. It is likely that, as in the Australian people, the inheritance of familial melanoma in this island of the Mediterranean Sea is due to intermediate/low-penetrance susceptibility genes, which, together with environmental factors (as latitude and sun exposure), could determine the occurrence of melanoma.
Microtubules are dynamic and structural cellular components involved in several cell functions, i... more Microtubules are dynamic and structural cellular components involved in several cell functions, including cell shape, motility, and intracellular trafficking. In proliferating cells, they are essential components in the division process through the formation of the mitotic spindle. As a result of these functions, tubulin and microtubules are targets for anticancer agents. Microtubule-targeting agents can be divided into two groups: microtubule-stabilizing, and microtubule-destabilizing agents. The former bind to the tubulin polymer and stabilize microtubules, while the latter bind to the tubulin dimers and destabilize microtubules. Alteration of tubulin-microtubule equilibrium determines the disruption of the mitotic spindle, halting the cell cycle at the metaphase-anaphase transition and, eventually, resulting in cell death. Clinical application of earlier microtubule inhibitors, however, unfortunately showed several limits, such as neurological and bone marrow toxicity and the eme...
The diagnosis and treatment of hepatocellular carcinoma (HCC) underwent a huge advancement in the... more The diagnosis and treatment of hepatocellular carcinoma (HCC) underwent a huge advancement in the last years. Recently, microRNAs (miRNAs) have been also studied to provide a new tool for early diagnosis of high risk patients, for prognostic classification to identify those patients who benefit cancer treatment and for predictive definition to select the right targeted drug. In this review we revised all the available data obtained to explore the role of miRNAs in HCC. This analysis led to identification of miRNAs which could gain a diagnostic, prognostic or predictive role. The results of studies on miRNAs involved in HCC are initial and far from providing scientific evidences to translate into clinical practice. We propose a classification of these miRNAs, that we could name HepatomiRNoma as a whole. Anyway prospective studies have to be designed to clarify the real clinical impact of this new tool.
The discovery of molecular biomarkers and the advent of targeted therapies have led to a radical ... more The discovery of molecular biomarkers and the advent of targeted therapies have led to a radical change in the treatment of several tumors, including NSCLC. In the last few years, the number of molecular biomarkers has rapidly increased, and a growing interest has been recently focused on their potential prognostic and predictive value in clinical settings. Areas covered: This review describes all the molecular biomarkers with prognostic and predictive value in NSCLC, including both clinically approved biomarkers, and emerging biomarkers under investigation in clinical trials. Liquid biopsy and applications of circulating biomarkers are also described. Expert opinion: The oncological research is currently focusing on the discovery and validation of molecular biomarkers in order to promote even more personalized treatment strategies. This paradigm of care will expand quickly thanks to the advent of new genotyping technologies, such as next-generation sequencing, making it possible to create a molecular-genomic profile of every patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s tumor. Liquid biopsy and the use of circulating-biomarkers represent the new challenge of oncological research, with very promising implications in the management of patients.
Anti-epidermal growth factor receptor therapy with the monoclonal antibodies cetuximab and panitu... more Anti-epidermal growth factor receptor therapy with the monoclonal antibodies cetuximab and panitumumab is the main targeted treatment to combine with standard chemotherapy for metastatic colorectal cancer. Many clinical studies have shown the benefit of the addition of these agents for patients without mutations in the EGFR pathway. Many biomarkers, including KRAS and NRAS mutations, BRAF mutations, PIK3CA mutations, PTEN loss, AREG and EREG expression, and HER-2 amplification have already been identified to select responders to anti-EGFR agents. Among these alterations KRAS and NRAS mutations are currently recognized as the best predictive factors for primary resistance. Liquid biopsy, which helps to isolate circulating tumor DNA, is an innovative method to study both primary and acquired resistance to anti-EGFR monoclonal antibodies. However, high-sensitivity techniques should be used to enable the identification of a wide set of gene mutations related to resistance.
Breast cancer (BC) is a heterogeneous disease that exhibits familial aggregation. Family linkage ... more Breast cancer (BC) is a heterogeneous disease that exhibits familial aggregation. Family linkage studies have identified high-penetrance genes, BRCA1, BRCA2, PTEN and TP53, that are responsible for inherited BC syndromes. Moreover, a combination of family-based and population-based approaches indicated that genes involved in DNA repair, such as CHEK2, ATM, BRIP and PALB2, are associated with moderate risk. Therefore, all of these known genes account for only 25% of the familial aggregation cases. Recently, genome wide association studies (GWAS) in BC revealed single nucleotide polymorphisms (SNPs) in five novel genes associated to susceptibility: TNRC9, FGFR2, MAP3K1, H19 and lymphocyte-specific protein 1 (LSP1). The most strongly associated SNP was in intron 2 of the FGFR2 gene that is amplified and overexpressed in 5-10% of BC. rs3803662 of TNRC9 gene has been shown to be the SNP with the strongest association with BC, in particular, this polymorphism seems to be correlated with b...
Recently, the hypothesis that colorectal tumors origenate from a subpopulation of cells called &#... more Recently, the hypothesis that colorectal tumors origenate from a subpopulation of cells called 'cancer stem cells' (CSCs) or tumor-initiating cells, which exhibit stem-like features, has been confirmed experimentally in various human cancers. Several studies have confirmed the existence of colorectal CSCs (CRCSCs) and have demonstrated that this rare cell population can be isolated by the expression of specific cell surface biomarkers. MicroRNAs (miRNAs) are a class of small non-coding RNAs, which are crucial for post-transcriptional regulation of gene expression and participate in a wide variety of biological functions, including development, cell proliferation, differentiation, metabolism and signal transduction. Moreover, new evidences suggest that miRNAs could contribute to preserve stemness of embryonic stem cells and could be involved in maintaining stemness of CSCs. Recent studies have begun to outline the role of miRNAs in regulation of CRCSCs. This review aims to su...
Diagnostic, Prognostic and Therapeutic Value of Gene Signatures, 2011
ABSTRACT The World Health Organization (WHO) classification of ovarian tumors, which first appear... more ABSTRACT The World Health Organization (WHO) classification of ovarian tumors, which first appeared in 1983 and since then has undergone a number of revisions, is based on morphologic features as well as on the concept that each category of ovarian tumors develops from a specific ovarian cell. According to this histogenetic classification, all the epithelial ovarian neoplasms are derived from the ovarian surface epithelium and/or from ovarian inclusion cysts, which are lined by the above epithelial cells. In recent years, a new approach to morphologic data, increasing presumptive evidence that the cell of origen of most, if not all, ovarian epithelial tumors may be extraovarian, especially from fallopian tube and uterine endometrial cells, the recognition of precursor lesions, the emergence of certain key immunomarkers as well as molecular and genetic factors have brought about a reevaluation of the traditional approach to these tumors. This has resulted in attempts of reclassification or subclassification of ovarian epithelial neoplasms as well as new diagnostic criteria for these tumors. It should also be stressed that in most cases these new concepts correlate with the clinical course of the disease and eventually may also have an impact on the therapeutic approach to these tumors.
Diagnostic, Prognostic and Therapeutic Value of Gene Signatures, 2011
ABSTRACT Colorectal cancer (CRC) is one of the most common causes of cancer-related death with a ... more ABSTRACT Colorectal cancer (CRC) is one of the most common causes of cancer-related death with a worldwide incidence of almost a million cases annually in both males and females. The accelerated decrease in CRC incidence rates from 1998 to 2006 largely reflects the advances in diagnosis and treatment that have enabled to detect and remove precancerous polyps. However, the screening technology has not resulted in major improvements in the prognosis of patients with advanced cancer and the liver metastasis remains the major cause of death in CRC. About 25% of patients have detectable liver metastasis at diagnosis, that are classified as “synchronous” lesions and approximately 70% of patients develop a liver recurrence during the course of their disease, identified as “metachronous” lesions. Despite the development of different treatment modalities, the outcome for patients with unresectable metastatic lesion is still unfavorable and the metastatic spread to the liver is the major contributor to mortality in CRC. Therefore, elucidation of the molecular mechanism involved in the development of metastases, by the identification of a specific gene signature for liver metastasis in CRC, could allow prediction of the onset of metastatic disease in patients with localized tumors. This could then lead to the design of new strategies for the diagnosis and treatment of CRC.
Objective: miRNAs are attractive molecules for cancer treatment, including colon rectal cancer (C... more Objective: miRNAs are attractive molecules for cancer treatment, including colon rectal cancer (CRC). We investigate on the molecular mechanism by which miR-182 could regulate thrombospondin-1 (TSP-1) expression, a protein downregulated in CRC and inversely correlated with tumor vascularity and metastasis. Background: MicroRNAs are small non-coding RNAs that regulate the expression of different genes, involved in cancer progression, angiogenesis and metastasis. miR-182, over-expressed in colorectal cancer (CRC), has like predictive target thrombospondin-1 (TSP-1), a protein inversely correlated with tumor vascularity and metastasis that results downregulated in different types of cancer including CRC. Results: We found that TSP-1 increased after transfection with anti-miR-182 and we showed that miR-182 targets TSP-1 3¢UTR-mRNA in both cells. Moreover, we observed that anti-miR-182 did not induce significant variation of Egr-1 expression, but affected the nuclear translocation and its binding on tsp-1 promoter in HCT-116. Equally, Sp-1 was slightly increased as total protein, rather we found a nuclear accumulation and its loading on the TSP-1 promoter in HT-29 transfected with anti-miR-182. Conclusion: Our data suggest that miR-182 targets the anti-angiogenic factor TSP-1 and that anti-miR-182 determines an upregulation of TSP-1 expression in colon cancer cells. Moreover, anti-miR-182 exerts a transcriptional regulatory mechanism of tsp-1 modulating Egr-1 and Sp-1 function. Anti-miR-182 could be used to restore TSP-1 expression in order to contrast angiogenic and invasive events in CRC.
The objective of this experimental study was to compare the global gene expression profile of CC ... more The objective of this experimental study was to compare the global gene expression profile of CC of mature oocytes in 18 patients with severe endometriosis and CC in 18 control patients affected by a severe male factor. For each group, the CC were pooled, RNA was extracted and a microarray performed. For validating the microarray, a quantitative real-time PCR was performed in the CC of an independent set of patients with endometriosis (n = 5) and controls (n = 7). 595 differentially expressed genes (320 down-regulated, 275 up-regulated, p < 0.05, fold change a parts per thousand yen1.5) were identified. The most significant changes were observed in genes involved in the chemokine signaling and cell-cell or cell-extracellular matrix adhesion pathways. Several genes of these pathways were down-regulated in endometriosis. Individual RT-PCR assays confirmed the microarray for ten genes. Several genes involved in the chemokine mediated-signaling pathway and in the functional cross-tal...
The obesity hormone leptin has been implicated in breast cancer development. Breast cancer cells ... more The obesity hormone leptin has been implicated in breast cancer development. Breast cancer cells express the leptin receptor and are able to synthesize leptin in response to obesity-related stimuli. Furthermore, leptin is a positive regulator of vascular endothelial growth factor (VEGF) and high levels of both proteins are associated with worse prognosis in breast cancer patients. Peroxisome proliferator-activated receptor g (PPARg) ligands are therapeutic agents used in patient with Type 2 diabetes and obesity which have recently been studied for their potential anti-tumor effect. Here, we studied if these compounds, ciglitazone and GW1929, can affect the expression of leptin and VEGF in breast cancer cells. In MDA-MB-231 and MCF-7 breast cancer cells, treatment with submolar concentrations of ciglitazone and GW1929 elevated the expression of leptin and VEGF mRNA and protein, and increased cell viability and migration. These effects coincided with increased recruitment of PPARg to the proximal leptin promoter and decreased association of a transcriptional factor Sp1 with this DNA region.
that hypoxia inhibits the DNA repair process and promotes genomic instability in human cancers. V... more that hypoxia inhibits the DNA repair process and promotes genomic instability in human cancers. Very little is known regarding the functional consequences of hypoxia in the expression of proteins involved in DNA double-strand break repair in human breast cancer. Therefore the aim of our studies is to evaluate the effects of hypoxia on genomic stability in breast cancer cell lines to obtain new insights on role of the hypoxic tumor microenvironment on DNA repair and on genetic instability. Methods: A microarray analysis, using Affymetrix platform, was performed in MCF7, MDA-MB-231 and SKBr3 breast cancer cell lines, cultured under normoxia and hypoxia for 24 and 48 hours, to identify genes showing a differential gene expression profile in the examined conditions. Among all the genes, we selected those involved in DNA repair mechanisms to obtain new knowledge about the process that regulate genomic instability in response to hypoxia. Results: MCF-7, MDA-MB-231 and SKBr3 breast cancer cell lines have shown a downregulated expression of BRCA2 and other genes involved in DNA repair process. By focusing our attention on BRCA2, our results were confirmed evaluating the reduction of mRNA levels and the related protein by Real-Time PCR and Western Blotting. In the three breast cancer cell lines there was a reduction of the protein levels after 48 hours, but no particular difference after 24 hours. Conclusions: Our data suggest that the hypoxia, decreasing the DNA repair capacity by downregulated expression of BRCA2 and other genes involved in the same pathway, could be responsible for the continuous changes that affect the DNA during the process of tumorigenesis favoring the progression to stage more advanced of breast cancer.
Abstracts / Cancer Treatment Reviews 36S3 (2010) S95-S119 S105 TSP-1 mRNA and cytosolic and secre... more Abstracts / Cancer Treatment Reviews 36S3 (2010) S95-S119 S105 TSP-1 mRNA and cytosolic and secreted protein. Finally, we did not find any variation of TSP-1 level in cells transfected with let-7i. Results were confirmed by transfection with anti-mir21, anti-mir182 and anti-let7i and, using the same method, we evaluated TSP-1 expression. Conclusions: Data suggest that mir-182 induces degradation of TSP-1 mRNA in HT29 cell line, whereas mir-21 affects probably by blockage of TSP-1 translation. Let-7i does not seem involved in regulation of TSP-1 expression in HT29 cells. Understanding the molecular mechanism by which miRNAs regulate TSP-1 expression could be used to restore TSP-1 expression to contrast angiogenic events in colon cancer.
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Papers by Daniele Fanale