Therapeutic implications of Cancer Initiating Cells.

2009

Background: Until few years ago, all neoplastic cells within a tumour were suggested to have tumorigenic capacity, but recent evidences hint to the possibility that such feature is confined to a subset of Cancer Initiating Cells (CICs), also called Cancer Stem Cells (CSCs). These cells are the reservoir of the heterogeneous populations of differentiated cancer cells constituting the tumour bulk. Mechanisms shared with somatic stem cells, such as quiescence, self-renewal ability, asymmetric division and multidrug resistance, allow to these cells to drive tumour growth and to evade conventional therapy. Objective: Here, we give a brief overview on the origin of CICs, the mechanisms involved i…

Pharmacogenomics in colorectal carcinomas: Future perspectives in personalized therapy

2005

The recent introduction of new drugs such as capecitabine, irinotecan, and oxaliplatinum has greatly improved the clinical outcome of patients with advanced/metastatic colorectal cancer. Nevertheless, some patients may suffer from the adverse drug reactions which will probably be the main cause of chemotherapy failure. The goal of pharmacogenomics is to find correlations between therapeutic responses to drugs and the genetic profiles of patients; the different responses to a particular drug are due, in fact, not only to the specific clinico-pathological features of the patient or to environmental factors, but also to the ethnic origins and the particular individual's genetic profile. Genes …

Isolation and Culture of Colon Cancer Stem Cells

2008

Cancer stem cells (CSCs) resemble normal stem cells in several ways. Both cell types are self-renewing and when they divide, one of the daughter cells differentiates while the other retains stem cell properties, including the ability to divide in the same way again. CSCs have been demonstrated to exist in several solid tumors, including colon carcinoma; these cells are able to initiate and sustain tumor growth. There are essentially three different methods to isolate CSCs: establishment culture, the MACS (magnetic cell sorting) technology, and the FACS (fluorescence-activated cell sorting) technology.

Bone morphogenetic protein 4 induces differentiation of colorectal cancer stem cells and increases their response to chemotherapy in mice.

2010

BACKGROUND & AIMS: The limited clinical response observed in many patients with colorectal cancer may be related to the presence of chemoresistant colorectal can- cer stem cells (CRC-SCs). Bone morphogenetic protein 4 (BMP4) promotes the differentiation of normal colonic stem cells. We investigated whether BMP4 might be used to induce differentiation of CRC-SCs and for therapeutic purposes. METHODS: CRC-SCs were isolated from 25 tumor samples based on expression of CD133 or using a selection culture medium. BMP4 expression and activity on CRC-SCs were evaluated in vitro; progeny of the stem cells were evaluated by immunofluorescence, immuno- blot, and flow cytometry analyses. The potential …

A new germline mutation in BRCA1 gene in a sicilian family with ovarian cancer

2005

A group of 103 sicilian patients with hereditary and familiar breast and/or ovarian cancer were screened for Breast Cancer 1 gene (BRCA1) mutations by direct sequencing PCR products spanning the coding region and partial intronic regions of the BRCA1 gene. In this study, we report a new germline mutation in BRCA1 gene, not previously reported in the BIC database, in a woman with ovarian cancer at 46 years old. Mother's proband has been diagnosed the same histotype of ovarian cancer at 42 age. The mutational analyses that shown a 4843delC frameshift mutation in exon 16 of BRCA1 gene was extended to other family members including the proband's brother and her two sons. Direct automatic sequen…

Aurora-A Is Essential for the Tumorigenic Capacity and Chemoresistance of Colorectal Cancer Stem Cells

2010

Abstract Colorectal cancer stem cells (CR-CSC) are responsible for the generation and maintenance of intestinal tumors and are highly resistant to conventional chemotherapeutic agents. Aurora-A, a serine-threonine kinase involved in mitosis regulation, plays multiple key functions in tumor initiation and progression. We found that Aurora-A is overexpressed in primary colorectal tumor cells, in the CR-CSC fraction, and in stem cell–derived differentiated cells, compared with normal colon tissue. Aurora-A expression was functionally linked to centrosome amplification in CR-CSC, as indicated by the decrease in cells with multiple centrosomes that followed Aurora-A silencing. Knockdown of Auror…

DNA ploidy and S-phase fraction, but not p53 or NM23-H1 expression, predict outcome in colorectal cancer patients. Result of a 5-year prospective stu…

2002

Purpose: The aim of this study was to determine TP53 and NM23-H1 immunoreactivity, DNA ploidy, and S-phase fraction (SPF) in a series of 160 patients undergoing resective surgery for primary operable colorectal cancer (CRC) and to establish whether these alterations have any clinical value in predicting CRC patients' prognosis. Methods: TP53 and NM23-H1 expressions were evaluated on paraffin-embedded tissue by immunohistochemistry and DNA-ploidy and SPF on frozen tissue by flow-cytometric analysis. Results: The median follow-up time in our study group was 71 months (range 34-115 months). P53 protein expression was associated with distal tumors (P < 0.05) and DNA aneuploid tumors (P < …

Tumorigenic and metastatic activity of human thyroid cancer stem cells

2010

Abstract Thyroid carcinoma is the most common endocrine malignancy and the first cause of death among endocrine cancers. We show that the tumorigenic capacity in thyroid cancer is confined in a small subpopulation of stem-like cells with high aldehyde dehydrogenase (ALDHhigh) activity and unlimited replication potential. ALDHhigh cells can be expanded indefinitely in vitro as tumor spheres, which retain the tumorigenic potential upon delivery in immunocompromised mice. Orthotopic injection of minute numbers of thyroid cancer stem cells recapitulates the behavior of the parental tumor, including the aggressive metastatic features of undifferentiated thyroid carcinomas, which are sustained by…

Nm-23-H1 expression does not predict clinical survival in colorectal cancer patients

2003

The gene Nm23, which encodes for a nucleoside diphosphate kinase, has been defined as a metastasis-suppressor gene because of the inverse correlation between its expression and the metastatic capacity of the tumor cells. For colorectal cancer, however, the findings are equivocal. The aim of our study was to assess, in 160 patients undergoing surgery for colorectal cancer (CRC), the expression of the Nm23-H1 protein and to evaluate its possible associations with traditional clinicopathologic variables, with DNA-ploidy and proliferative activity (S-phase fraction, SPF), and with disease-free and overall survival of patients. Nm23-H1 expressions were evaluated on paraffin-embedded tissue by im…

Colon Cancer Stem Cells Dictate Tumor Growth and Resist Cell Death by Production of Interleukin-4

2007

A novel paradigm in tumor biology suggests that cancer growth is driven by stem-like cells within a tumor. Here, we describe the identification and characterization of such cells from colon carcinomas using the stem cell marker CD133 that accounts around 2% of the cells in human colon cancer. The CD133(+) cells grow in vitro as undifferentiated tumor spheroids, and they are both necessary and sufficient to initiate tumor growth in immunodeficient mice. Xenografts resemble the original human tumor maintaining the rare subpopulation of tumorigenic CD133(+) cells. Further analysis revealed that the CD133(+) cells produce and utilize IL-4 to protect themselves from apoptosis. Consistently, trea…

TP53 and p16INK4A, but not H-KI-Ras, are involved in tumorigenesis and progression of pleomorphic adenomas.

2006

The putative role of TP53 and p16INK4A tumor suppressor genes and Ras oncogenes in the development and progression of salivary gland neoplasias was studied in 28 cases of pleomorphic adenomas (PA), 4 cases of cystic adenocarcinomas, and 1 case of carcinoma ex-PA. Genetic and epigenetic alterations in the above genes were analyzed by Polymerase Chain Reaction/Single Strand Conformational Polymorphism (PCR/SSCP) and sequencing and by Methylation Specific-PCR (MS-PCR). Mutations in TP53 were found in 14% (4/28) of PAs and in 60% (3/5) of carcinomas. Mutations in H-Ras and K-Ras were identified in4%(1/28) and7% (2/28) of PAs, respectively. Only 20% (1/5) of carcinomas screened displayed mutatio…

TP 53, H-K-Ras, P16INK4A gene molecular analysis in salivary gland tumors.

2006

Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4

2008

We investigated the mechanisms involved in the resistance to cell death observed in epithelial cancers. Here, we identify that primary epithelial cancer cells from colon, breast and lung carcinomas express high levels of the antiapoptotic proteins PED, cFLIP, Bcl-xL and Bcl-2. These cancer cells produced interleukin-4 (IL-4), which amplified the expression levels of these antiapoptotic proteins and prevented cell death induced upon exposure to TRAIL or other drug agents. IL-4 blockade resulted in a significant decrease in the growth rate of epithelial cancer cells and sensitized them, both in vitro and in vivo, to apoptosis induction by TRAIL and chemotherapy via downregulation of the antia…

DNA aneuploidy, high SPF and specific p53 mutations are independent prognostic factors in colorectale cancer (CRC)

2004

DNA-aneuploidy and high SPF and specific p53 mutations are independent prognostic factors in colorectal cancer (CRC).

2004

TP53 Mutation in exon 5 and S-Phase Fraction but not Mutations in Ras gene family and DNA-ploidy are Indipendent prognostic indicators in Laryngeal S…

2005

Fattori Predittivi di Risposta ai Citostatici nei Tumori del Tratto Gastrointestinale

2004

Role of K-RAS and P53 Gene in Salivary Glands Tumorigenesis

2004

Isolation and culture of colon cancer stem cells.

2008

Cancer stem cells (CSCs) resemble normal stem cells in several ways. Both cell types are self-renewing and when they divide, one of the daughter cells differentiates while the other retains stem cell properties, including the ability to divide in the same way again. CSCs have been demonstrated to exist in several solid tumors, including colon carcinoma; these cells are able to initiate and sustain tumor growth. There are essentially three different methods to isolate CSCs: establishment culture, the MACS (magnetic cell sorting) technology, and the FACS (fluorescence-activated cell sorting) technology.

Fattori predittivi di risposta ai citostatici nei tumori del tratto gastrointestinale. In A Zaniboni “ I tumori del tratto gastroenterico” pag 31-37,…

2004

TP53 mutations are not prognostic indipendent indicators in bladder cancer

2005

The prognostic role of TP53 mutations in advanced laryngeal squamous cell carcinoma (LSCC).

2005

Analysis of Ki-ras mutations in stage I rectal carcinomas and respective regional lymphonodes

2005

RUOLO DI P53 E DEI GENI K-RAS EDH-RAS NELLA TUMORIGENESI DELLE GHIANDOLE SALIVARI

2004

Role of interleukin-4 on colon cancer stem cell survival

2009

TP53 in exon 5 and s-Phase fraction but not mutations in Ras gen family and DNA-ploidy are indipendent indicators in laryngeal squamous cell carcinoma

2005

Mutational analysis of BRCA1 gene in sicilian patient at risk for inherited breast and/or ovarian cancer: experience of reference center the biomolec…

2005

Detection and clinical relevance of free-circulating tumor DNA in blood of patients with colorectal cancer

2004

TP53 mutations are not prognostic independent indicators in bladder cancer.

2005

TP53 mutation are not prognostic indipendent indicators in bladder cancer

2005

Detection and clinical relevance of free circulating tumor DNA in blood of patients with gastrointestinal cancer

2004

TP53, H-K-RAS, P16INK4A GENE MOLECULAR ANALYSIS IN SALIVARY GLAND TUMORS

2007

Detection of free-circulating tumor DNA in plasma of patients with gastrointestinal cancer.

2005

DNA-Aneuploidy, High SPF and Specific P53 Mutations are Indipendent Prognostic Factors in Colorectal Cancer (CRC)

2004

A.Mutational analysis of BRCA1 in sicilian patients at risk for inherited of reference center for the biomolecular characterizaztion of neoplasm and …

2005

RUOLO DI P53 E DEI GENI K-RAS ED H-RAS NELLA TUMORIGENESI DEI CARCINOMI DELLE GHIANDOLE SALIVARI

2004

Detection and clinical relevance of free-circulating tumor DNA in blood of patients with colorectal cancer. Proceeding of ICACT Fifteenth Internation…

2004

Mutational analysis of BRCA1 gene in sicilian patients at risk for inherited breast and/or ovarian cancer: experience of reference centre for the bio…

2005

TP53 mutations and S-Phase fraction are independent prognostic indicators in locally advanced laryngeal squamous cell carcinoma

2005

Larynx tumor is a rare neoplasia that represent only the 2% of all human tumor. In particular, the 90% of tumor that occur in this organ correspond to the laryngeal squamous cell carcinoma (LSCC). From the biomolecular point of view, it was shown that the TP53 gene mutations are the most common events observed in the early phases of LSCC carcinogenesis. However, them prognostic significance remains controversial. Besides, the prognostic significance of DNA ploidy has been well established for other solid tumors, but its role in LSCC is still controversial. The aim of this study was, therefore, to prospectively evaluate the prognostic significance of TP53 mutations, DNA-ploidy and S-phase fr…