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Biomedical subjects

C Cillo

Publications and source records attributed to C Cillo.

At least 19 recordsLinked to original sources
PubMed2005

cAMP induced modifications of HOX D gene expression in prostate cells allow the identification of a chromosomal area involved in vivo with neuroendocrine differentiation of human advanced prostate cancers.

The acquisition of epithelial-neuroendocrine differentiation (ND) is a peculiarity of human advanced, androgen-independent, prostate cancers. The HOX genes are a network of transcription factors controlling embryonal development and playing an important role in crucial adult eukaryotic cell functions. The molecular organization of this 39-gene network is unique in the genome and probably acts by regulating phenotype cell identity. The expression patterns of the HOX gene network in human prostate cell phenotypes, representing different stages of prostate physiology and prostate cancer progression, make it possible to discriminate between different human prostate cell lines and to identify loci and paralogous groups harboring the HOX genes mostly involved in prostate organogenesis and cancerogenesis. Exposure of prostate epithelial phenotypes to cAMP alters the expression of lumbo-sacral HOX D genes located on the chromosomal region 2q31-33 where the cAMP effector genes CREB1, CREB2, and cAMP-GEFII are present. Interestingly, this same chromosomal area harbors: (i) a global cis-regulatory DNA control region able to coordinate the expression of HOX D and contiguous phylogenetically unrelated genes; (ii) a prostate specific ncRNA gene associated with high-risk prostate cancer (PCGEM1); (iii) a series of neurogenic-related genes involved with epithelial-neuronal cell conversion. We report the expression of neurexin 1, Neuro D1, dlx1, and dlx2 in untreated and cAMP treated epithelial prostate cells. The in vivo expression of Neuro D1 in human advanced prostate cancers correlate with the state of tumor differentiation as measured by Gleason score. Thus, we suggest that the chromosomal area 2q 31-33 might be involved in the epithelial-ND characteristic of human advanced prostate cancers.

Bucladesine↗
PubMed2003

In vivo expression of the whole HOX gene network in human breast cancer.

The HOX network contains 39 genes that act as transcriptional regulators and control crucial cellular functions during both embryonic development and adult life. Inside the network, this is achieved according to the rules of temporal and spatial co-linearity with 3' HOX genes acting on the anterior part of the body, central HOX genes on the thoracic part and lumbo-sacral HOX genes on the caudal region. We analysed HOX gene expression in normal breast tissue and in primary breast cancers by reverse-transcriptase-polymerase chain reaction (RT-PCR). 17 out of 39 HOX genes were expressed in the normal breast tissue. The expression of thoracic HOX genes tended to be similar in normal and neoplastic breast tissues suggesting that these genes are involved in breast organogenesis. In contrast, cervical and lumbo-sacral HOX gene expression was altered in the primary breast cancers with respect to normal breast tissue. This supports their involvement in breast cancer evolution and suggests they could be targets for future cancer therapies.

Adult↗
PubMed2003

[The cellular and molecular bases of "tooth framing"].

Progress in molecular biology in recent years has enormously increased interest in tooth generation. The enamel knot has been discovered, in consequence. This is a transient structure acting as molecular signaling center, responsible for controlling cusp formation, stimulating growth of surrounding epithelium, and generating new knots or their disappearance through apoptosis. Both tooth development and enamel knots are regulated by a cascade of gene activity where Fgf4, Shh, BMP4, Lef1 and p21 are the prime movers of the processes. Homeobox genes (Msx, Dlx) are the orchestrators of the framing and a series of proteins (adhesion molecules, extracellular matrix components) are the executors of "tooth framing". An important concept has emerged from developmental biology through the identification of the basic mechanisms involved in tooth development: the molecular basis of structure framing shares common rules. Thus similar genetic programs are involved in body structure generation (limb bud, tooth, branching morphogenesis). A deeper understanding of developmental rules regulating tooth formation will make it possible in the near future: a) to modify in vivo homeobox gene expression and restore tooth generation hampered by tooth agenesia due to homeobox gene deregulation; b) to induce complete tooth formation, in case of tooth loss due to trauma or diseases, through implantation in the patient's oral cavity of a synthetic ball containing morphogens and growth factors to stimulate, in the right spatio-temporal sequence, the entire tooth genetic cascade. These concepts will certainly enforce cultural and practical interaction between biology and dentistry.

Animals↗
PubMed2001

Homeobox genes in normal and malignant cells.

Homeobox genes are transcription factors primarily involved in embryonic development. Several homeobox gene families have so far been identified: Hox, EMX, PAX, MSX as well as many isolated divergent homeobox genes. Among these, Hox genes are most intriguing for having a regulatory network structure organization. Recent indications suggest the involvement of homeobox genes in (i) crucial adult eukariotic cell functions and (ii) human diseases, spanning from diabetes to cancer. In this review we will discuss the mechanisms through which homeobox genes act, and will propose a model for the function of the Hox gene network as decoding system for achieving specific genetic programs. New technologies for whole-genome RNA expression will be crucial to evaluate the clinical relevance of homeobox genes in structural and metabolic diseases.

Animals↗
PubMed1999

Homeobox genes and cancer.

Homeobox-containing genes are a family of regulatory genes encoding transcription factors that primarily play a crucial role during development. Several indications suggest their involvement in the control of cell growth and, when dysregulated, in oncogenesis. We will describe the implications, in tumor origin and evolution, of members of the homeobox gene families HOX, EMX, PAX, and MSX as well as of other divergent homeobox genes. We will also propose a model for the function of the HOX gene network in controlling cell identity to account for the involvement of some HOX genes in both normal development and oncogenesis.

Animals↗
PubMed1996

Differential patterns of HOX gene expression are associated with specific integrin and ICAM profiles in clonal populations isolated from a single human melanoma metastasis.

Homeobox-containing genes comprise a gene family coding for transcription factors involved in normal development. Class I human homeobox (HOX) genes display a peculiar chromosomal organization, perhaps directly related to their function. Aberrant expression of homeobox genes has been associated with both morphological abnormalities and oncogenesis. We have reported that HOX gene expression is (i) specific for normal adult human organs (kidney, colon, lung) and (ii) altered in cancer specimens according to their histological type and stage of tumor progression. Here, we have investigated whether patterns of HOX gene expression are associated with tumor heterogeneity by analyzing the expression of the entire panel of 38 HOX genes in clones isolated from a single human metastatic melanoma call line (Me 665/2). The differential expression of a block of genes located at the 5' end of the HOX C locus allows melanoma clones to be classified into 2 major groups. The 2 patterns of HOX gene expression are inversely associated with 2 distinct surface phenotypes for integrins (VLA-2, VLA-5 and VLA-6) and the adhesion molecule ICAM-1. The genes of the HOX C locus are silent in the clones with high levels of integrins VLA-2, VLA-5 and VLA-6 and of the adhesion molecule ICAM-1 but actively expressed in the clones with low levels of ICAM-1 and lacking VLA-2, VLA-5 and VLA-6. Our results indicate that HOX gene expression reflects the intra-tumor heterogeneity of melanoma clones and suggest that the expression of surface molecules involved in cell-cell and cell-matrix interactions may be related to the patterns of HOX gene expression.

Adult↗
PubMed1996

Relationship between DNA methylation and gene expression of the HOXB gene cluster in small cell lung cancers.

The expression pattern of the HOXB gene cluster in four xenografted small-cell lung cancers was compared to the methylation of the DNA in the corresponding genomic regions. In 90% (17/19) of the studied cases, the expressed genes were in methylated regions whereas 70% (12/17) of the unexpressed genes were in unmethylated regions. This specific behavior could correspond to a particular gene expression regulation mechanism of the HOX gene network. Since some genes (HOXB2, HOXB4, HOXB7) were always inactive when unmethylated, this unexpected relationship might indicate their key function(s) in the HOX gene network.

Animals↗
PubMed1996

Fine mapping of human HOX gene clusters.

The chromosome localization of human HOX gene clusters has been reinvestigated by fluorescence in situ hybridization (FISH). Three loci were precisely localized in 7p15.3 (HOXA@), 17q21.3 (HOXB@) and 12q13.3 (HOXC@). The localization of HOXD@ was confirmed to 2q31.

Cells, Cultured↗
PubMed1996

[Apropos of the studies of Lewis, Nusslein-Volhard and Wieschaus, 1995 Nobel prize winners, on the genetic mechanisms of embryonic development of drosophila. A model for human cancer progression].

EB Lewis, C Nusslein-Volhard and E Wieschaus were the winners of the Nobel prize in 1995 for the discovery of genes controling the embryonic development in drosophila. Drosophila development is dependent on sequential activities of three types of genes: the maternal genes, the segmentation genes, and the homeotic genes which are responsible for the segment identity and finally for the building of the body. Mutations of these genes are spectacular because they affect the body structure formed from individual segments. Therefore, the molecular processes regulating the development of inferior organisms such as yeast or more complex as the vertebrates were elucidated by these three researchers. These early biological mechanisms regulate the cell life through interactions with neighbouring cells. We speculate that any alteration of these processes might be implicated in cancer. Understanding of these molecular mechanisms which control cell interactions in cancer constitutes a basis for definition of new prognostic markers and putatively novel therapeutic approaches.

Animals↗
PubMed1994

HOX gene expression in human small-cell lung cancers xenografted into nude mice.

Transcription factors are crucial to an understanding of the molecular basis of neoplasia. Homeobox-containing genes are a family of transcriptional regulators encoding DNA-binding homeodomains, involved in the control of normal development. Class-I human homeobox-containing genes (HOX genes) display a peculiar chromosomal organization, perhaps directly related to their function. Aberrant expression of homeobox-genes has been associated with both morphological abnormalities and oncogenesis. We have recently observed that alterations in HOX gene expression are detectable in kidney and colon cancer when compared to the corresponding normal organs. Here we have analyzed the expression of HOX genes in primary and metastatic human small-cell lung cancer (SCLC) xenografted in nude mice, in order to investigate whether HOX gene expression correlates with the histology and stage of SCLC progression. The results show that different SCLCs display differential patterns of HOX gene expression. Furthermore, in SCLC, the number of actively expressed HOX genes might be substantially lower in metastatic cancers than in primary tumors. The alteration in HOX gene expression in SCLCs mainly concerns the HOX B and C loci. This finding suggests that downregulation of HOX genes may play a role in small-cell lung cancer progression, possibly through their implication in tumor suppression.

Animals↗
PubMed1993

Characteristic patterns of HOX gene expression in different types of human leukemia.

Homeobox-containing genes are a network of genes encoding DNA-binding proteins highly conserved throughout evolution. They are involved in the control of normal development as well as in the regulation of gene expression in adult differentiating systems, including hematopoiesis. Aberrant expression of homeobox-containing genes has recently been related to leukemic phenotype. Human homeobox-containing genes of the HOX family are organized into 4 large clusters. We have analyzed the expression of HOX genes in different types of human leukemia to investigate whether the physical organization of HOX loci reflects a regulatory hierarchy involved in the differentiation of hematopoietic cells or whether HOX gene expression might contribute to the leukemic phenotype. Our results show that HOX genes are coordinately regulated in blocks in myeloid cells whereas they appear to function as isolated genes in lymphoid cells. Six contiguous genes of the HOX2 locus, highly expressed in acute non-lymphocytic leukemia, are switched off in chronic myelogenous leukemia, suggesting that down-regulation of HOX2 genes might be required for cell maturation of the myeloid lineages. In contrast, a few scattered genes are active in lymphoid populations. These observations suggest that hematopoietic cells express a repertoire of HOX genes characteristic of a particular cell lineage at a specific stage of differentiation. The characteristic patterns of HOX gene expression may reflect the potentially important role that these genes play in cell lineage determination during both normal and leukemic hematopoiesis.

Cell Differentiation↗
PubMed1993

Expression of homeobox-containing genes in primary and metastatic colorectal cancer.

Homeobox genes are a network of genes encoding nuclear proteins functioning as transcriptional regulators. Human and murine homeobox genes of the HOX family are organised in four clusters on different chromosomes. Gene order within each cluster is highly conserved, perhaps in direct relation to their expression. Homeobox genes have recently been involved in normal development and oncogenesis. We have analysed HOX gene expression in normal human colon and in primary and metastatic colorectal carcinomas. The majority of HOX genes are active in normal adult colon and their overall expression pattern is characteristic of this organ. Furthermore, the expression of some HOX genes is identical in normal and neoplastic colon indicating that these genes may exert an organ-specific function. In contrast, other HOX genes exhibit altered expression in primary colon cancers and their hepatic metastases which may suggest an association with colon cancer progression.

Colon↗
PubMed1992

HOX gene expression in normal and neoplastic human kidney.

As a consequence of transformation, cancer cells generally lose some of their differentiative properties. Thus, alterations interfering with the genetic mechanisms required to maintain embryonic determination could lead to tumorigenesis. Homeobox genes are a network of genes encoding nuclear proteins containing DNA-binding homeodomains that are highly conserved throughout evolution. They are expressed in a stage-related fashion in the developing embryo and, in adult life, in normal tissues. In mice and humans, homeobox genes of the HOX family are organized in 4 clusters on different chromosomes which have presumably evolved by duplication of a primordial gene cluster. Strikingly, the order of genes within each cluster is also highly conserved throughout evolution, suggesting that the physical organization of HOX genes might be essential for their expression. Recent reports indicate that homeobox mutant mice display morphological abnormalities or show neoplastic alterations, and that growth factors can turn on homeobox genes. We have studied the expression of the Antennapedia-like HOX genes in normal human kidney and in renal carcinomas. The great majority of the HOX genes analyzed are expressed in a peculiar manner in normal kidney: blocks of genes, even entire HOX loci, are coordinately regulated. Alterations in HOX gene expression in renal carcinoma can be observed in 2 genes of the HOX-2 locus, HOX-2A and HOX-2E, which are actively expressed in normal kidney and silent in cancer biopsies. The HOX-3H gene is not expressed in normal kidney whereas the HOX-3H transcripts are present in renal carcinomas. Homeobox genes within the 4 HOX loci can be aligned on the basis of the maximal sequence homology of their homeodomains: this alignment defines 13 paralogous gene groups. In renal carcinomas, genes of group 10 (HOX-1D, 2F, 3E, 4B) display a marked difference in their transcript classes when compared to those of normal kidney. Our findings suggest an association between altered HOX gene expression and kidney cancer.

Carcinoma, Renal Cell↗
PubMed1991

Coordinate regulation of HOX genes in human hematopoietic cells.

Hematopoiesis is a continuous process in which precursor cells proliferate and differentiate throughout life. However, the molecular mechanisms that govern this process are not clearly defined. Homeobox-containing genes, encoding DNA-binding homeodomains, are a network of genes highly conserved throughout evolution. They are organized in clusters expressed in the developing embryo with a positional hierarchy. We have analyzed expression of the four human HOX loci in erythroleukemic, promyelocytic, and monocytic cell lines to investigate whether the physical organization of human HOX genes reflects a regulatory hierarchy involved in the differentiation process of hematopoietic cells. Our results demonstrate that cells representing various stages of hematopoietic differentiation display differential patterns of HOX gene expression and that HOX genes are coordinately switched on or off in blocks that may include entire loci. The entire HOX4 locus is silent in all lines analyzed and almost all the HOX2 genes are active in erythroleukemic cells and turned off in myeloid-restricted cells. Our observations provide information about the regulation of HOX genes and suggest that the coordinate regulation of these genes may play an important role in lineage determination during early steps of hematopoiesis.

Cell Line↗
PubMed1989

Drug resistance in KHT fibrosarcoma cell lines with different metastatic ability.

We have shown previously that tumor cell variants able to form experimental metastases can be generated stochastically in mouse cell lines at high rates and that, in B16 melanoma cell lines, resistance to drugs is associated with metastatic ability. Recently, we reported on the ability of two lines of KHT fibrosarcoma cells derived from individual experimental lung metastases to generate metastatic variants. The KHT 35LI cell line maintained a relatively stable high metastatic ability while the parallel line KHT 3LIc possessed a high metastatic ability when first cultured from the lung but rapidly lost this ability and became a line with a metastatic ability similar to the KHT parental line. Subsequent rate analysis indicated that the rate of generation of metastatic variants was higher for KHT 35LI cells compared to KHT 3LIc or KHT parental cells. Here we examined the ability of these two fibrosarcoma cell lines to generate variants resistant to the drugs methotrexate (MTX) and N-(phosphonacetyl)-L-aspartate (PALA). We observed that the highly metastatic KHT 35LI cell line is more resistant to these two drugs than the KHT 3LIc or the parental KHT cell lines. Cloning studies indicated that the likely reason for this increased resistance is that the KHT 35LI cell line generates variants resistant to a given concentration of MTX or PALA at higher rates than the KHT 3LIc or KHT parental cell lines. Since resistance to MTX and PALA usually arises from gene amplification, the results suggest that KHT 35LI cells possess increased ability to amplify their DNA. The association between the rates of generation of both drug-resistant and metastatic variants supports the hypothesis that the mechanism of gene amplification may be involved in the generation of both phenotypes.

Animals↗
PubMed1987

Generation of drug-resistant variants in metastatic B16 mouse melanoma cell lines.

Genetic instability is recognized as an important aspect of the development of tumor heterogeneity and malignancy. In a previous study [Hill et al. Science (Wash. DC), 244:998-1001, 1984], we demonstrated that metastatic variants are generated at a more rapid rate in the highly metastatic B16F10 mouse melanoma cell line than in the less metastatic B16F1 cell line. The metastatic variants were phenotypically unstable, being generated and lost at high rates; consequently, we proposed a dynamic heterogeneity model of tumor metastasis which describes these properties quantitatively. As an extension of this work, we have examined the ability of these two melanoma cell lines to generate variants resistant to the drugs methotrexate and N-(phosphonacetyl)-L-aspartate. We observed that the highly metastatic B16F10 cell line generated variants resistant to a given concentration of methotrexate or N-(phosphonacetyl)-L-aspartate at higher rates than the B16F1 cell line. We conclude that B16F10 cells are genetically less stable than B16F1 cells and since resistance to methotrexate and N-(phosphonacetyl)-L-asparate usually results from gene amplification that B16F10 cells possess increased ability to amplify DNA. This higher rate of generation of drug-resistant variants corresponds to the higher rate of generation of metastatic variants we observed previously and suggests that a gene amplification mechanism may be involved in the generation of a metastic phenotype in B16 melanoma cells.

Animals↗