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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The central role of sequential accumulation of genetic alterations during the development of cancer has been firmly established since the pioneering cytogenetic studies successfully defined recurrent chromosome changes in specific types of tumor. In the course of carcinogenesis, cells experience several genetic alterations that are associated with the transition from a preneoplastic lesion to an invasive tumor and finally to the metastatic state. Tumor progression is characterized by stepwise accumulation of genetic alterations. So does the dominant metastatic clone. Modern molecular genetic analyses have clarified that genomic changes accumulate during the development and progression of cancers. In comparison with the corresponding primary tumor, additional events of chromosomal aberrations (including gains or allelic losses) are frequently found in metastases, and the incidence of combined chromosomal alterations in the primary tumor, plus the occurrence of additional aberrations in the distant metastases, correlated significantly with decreased postmetastatic survival. The deletions at 3p, 4p, 6q, 8p, 10q, 11p, 11q, 12p, 13q, 16q, 17p, 18q, 21q, and 22q, as well as the over-representations at 1q, 8q, 9q, 14q and 15q, have been found to associate preferentially with the metastatic phenotype of human cancers. Among of them, the deletions on chromosomes 8p, 17p, 11p and 13p seem to be more significant, and more detail fine regions of them, including 8p11, 8p21-12, 8p22, 8p23, 17p13.3, 11p15.5, and 13q12-13 have been suggested harboring metastasis-suppressor genes. During the past decade, several human chromosomes have been functionally tested through the use of microcell-mediated chromosome transfer (MMCT), and metastasis-suppressor activities have been reported on chromosomes 1, 6, 7, 8, 10, 11, 12, 16, and 17. However, it is not actually known at what stage of the metastatic cascade these alterations have occurred. There is still controversial with the association between the chromosomal aberrations and the metastatic phenotype of cancer. As the progression of human genome project and the establishment of more and more new techniques, it is hopeful to make clear the genetic mechanisms involved in the tumor metastasis in a not very long future, and provide new clues to predicting and controlling the metastasis.
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PMID:Chromosomal aberrations related to metastasis of human solid tumors. 1237 13

Matrix metalloproteinases (MMPs) have long been thought of as critical factors regulating matrix degradation associated with cell invasion into ectopic tissue compartments during primary tumor growth and metastasis. One member of the MMP family historically linked to these invasive processes is MMP-9/gelatinase B. By studying a transgenic mouse model of de novo epithelial carcinogenesis, new roles for MMP-9 have emerged that broaden the view of its functional contribution to malignant progression. The combined implication of these studies suggest that MMP-9 functionally contributes to cancer development; however, its major regulatory role may be in its ability to activate poorly diffusible and/or matrix-sequestered growth factors that regulate epithelial and/or endothelial cell growth as opposed to regulating cellular invasion across basement membranes.
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PMID:Epithelial carcinogenesis: dynamic interplay between neoplastic cells and their microenvironment. 1249 2

All-trans retinoic acid (atRA) has been suggested to exert its cytotoxicity via apoptosis but the mechanisms behind the damage effects have not been fully understood. In this study, we investigated the cytotoxic effects of atRA in eleven primary and matched metastatic cutaneous melanoma cell lines. All the primary and metastatic melanoma cell lines examined expressed the retinoic acid receptors. The cultured melanoma cells treated with atRA showed dysfunction of mitochondria and altered cell cycle distribution, inhibited cell proliferation and apoptosis. The cytotoxic effects of atRA were dose- and time-dependent. The dysfunction of mitochondria and induction of apoptosis were more pronounced in the primary tumor cells than in the metastatic cell lines from the same patients. The data indicate that the cytotoxic effect of atRA was mediated through dysfunction of mitochondria, alterations in cell cycle and induction of apoptosis. Melanoma in early stage may have better response to atRA adjuvant therapy than the melanoma in late stage, suggesting the early utility of atRA in melanoma chemotherapy.
Carcinogenesis 2003 Feb
PMID:All-trans retinoic acid (atRA) differentially induces apoptosis in matched primary and metastatic melanoma cells -- a speculation on damage effect of atRA via mitochondrial dysfunction and cell cycle redistribution. 1258 66

Differential gene methylation is observed in a variety of human malignancies. The study of the pattern of methylated genes helps to understand carcinogenesis and to identify potential marker tumor genes for clinical use. The differential methylated genes in undifferentiated nasopharyngeal carcinoma (NPC) of Chinese were studied by methylation-specific polymerase chain reaction (MSP). Methylation status of 11 tumor-associated genes (ARF, caspase-8, CDH1, CDKN2A, CDKN2B, MGMT, MLH1, RASSF1A, THBS1, TP73 and VHL) was studied in 30 primary undifferentiated NPC and paired peripheral blood of 12 patients. The methylation profile of NPC in order of frequency was CDH1 (50%), CDKN2B (50%), THBS1 (50%), RASSF1A (46%), MLH1 (40%), MGMT (28%), CDKN2A (23%), TP73 (20%), caspase-8 (7%), ARF (3%) and VHL (0%). Methylation of at least 1 gene was observed in 93% of primary NPC. Of the 12 patients with at least 1 methylated gene in the primary tumor, all 12 (100%) patients had at least 1 of the methylated gene promoter detectable in their peripheral blood. The results show high frequency of methylation in NPC and the potential of using methylation as peripheral blood tumor marker in screening NPC.
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PMID:Differential gene methylation in undifferentiated nasopharyngeal carcinoma. 1263 81

The concept of "field cancerization" was first introduced by Slaughter et al. [D. P, Slaughter et al., Cancer (Phila.), 6: 963-968, 1953] in 1953 when studying the presence of histologically abnormal tissue surrounding oral squamous cell carcinoma. It was proposed to explain the development of multiple primary tumors and locally recurrent cancer. Organ systems in which field cancerization has been described since then are: head and neck (oral cavity, oropharynx, and larynx), lung, vulva, esophagus, cervix, breast, skin, colon, and bladder. Recent molecular findings support the carcinogenesis model in which the development of a field with genetically altered cells plays a central role. In the initial phase, a stem cell acquires genetic alterations and forms a "patch," a clonal unit of altered daughter cells. These patches can be recognized on the basis of mutations in TP53, and have been reported for head and neck, lung, skin, and breast cancer. The conversion of a patch into an expanding field is the next logical and critical step in epithelial carcinogenesis. Additional genetic alterations are required for this step, and by virtue of its growth advantage, a proliferating field gradually displaces the normal mucosa. In the mucosa of the head and neck, as well as the esophagus, such fields have been detected with dimensions of >7 cm in diameter, whereas they are usually not detected by routine diagnostic techniques. Ultimately, clonal divergence leads to the development of one or more tumors within a contiguous field of preneoplastic cells. An important clinical implication is that fields often remain after surgery of the primary tumor and may lead to new cancers, designated presently by clinicians as "a second primary tumor" or "local recurrence," depending on the exact site and time interval. In conclusion, the development of an expanding preneoplastic field appears to be a critical step in epithelial carcinogenesis with important clinical consequences. Diagnosis and treatment of epithelial cancers should not only be focused on the tumor but also on the field from which it developed.
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PMID:A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications. 1270 51

Research into molecular and genetic mechanisms underlying prostate carcinogenesis would be greatly advanced by in vitro models of prostate tumors representing primary tumors. The generation of immortalized primary prostate cancer cells that will accurately reflect the in situ characteristics of malignant epithelium is greatly needed. We have successfully established a neoplastic immortalized human prostate epithelial (HPE) cell culture derived from a primary tumor. The RC-9 cells transduced through infection with a retrovirus vector expressing the E6 and E7 genes (E6E7) of human papilloma virus-16 (HPV-16) are currently growing well at passage 40, whereas RC-9 cells senesced at passage 7. RC-9/E6E7 cells exhibit epithelial morphology and high level of telomerase activity. More importantly, these immortalized cells produced tumors (SCID5038D) when inoculated into SCID mice. RC-9/E6E7 cells and SCID-5038D cells exhibit a high level of telomerase activity and androgen-responsiveness when treated with R1881. Expression of prostate specific antigen (PSA), androgen receptor (AR), prostate stem cell antigen (PSCA), an androgen-regulated prostate specific gene (NKX3.1), p16, cytokeratins 8, 15 and HPV-16 E6 gene was detected in both of these cells. RC-9/E6E7 and SCID5038D cells also showed growth inhibition when exposed to retinoic acid and transforming growth factor (TGF)-beta1, potent inhibitors of prostate epithelial cell growth. A number of chromosome alterations were observed including the loss of chromosomes 2p, 3p, 8p, 13, 14, 16, 17, 18, 21 and the gain of 7 and 20 in the tumor cell line (SCID5038D). These results demonstrate that this primary tumor-derived HPE cell line retained its neoplastic phenotypes and its prostate-specific markers and should allow studies to elucidate molecular and genetic alterations involved in prostate cancer. This is the first documented case of a malignant AR and PSA positive established human prostate cancer cell line from a primary tumor of a prostate cancer patient.
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PMID:A novel neoplastic primary tumor-derived human prostate epithelial cell line. 1273 99

Recent studies have revealed significant efficacy of the marine sponge glycolipid, alpha-galactosylceramide (alpha-GalCer), in treatment of experimental metastatic cancers, infections, and autoimmune diseases. However, the capacity of alpha-GalCer to prevent tumor development had never, to our knowledge, been evaluated in mouse models of chemical- and oncogene-dependent carcinogenesis. In this study, we demonstrate that long-term administration of soluble alpha-GalCer, spanning the time of tumor initiation, inhibits primary tumor formation in three different models: methylcholanthrene-induced sarcomas, mammary carcinomas in Her-2/neu transgenic mice, and spontaneous sarcomas in p53-/- mice. Weekly treatment of mice with alpha-GalCer maintained lymphoid tissue natural killer cell and T cell activation and elevated serum IFN-gamma and IL-4 concentrations. Consistent with the antimetastatic activity of alpha-GalCer, prevention of methylcholanthrene-induced sarcoma was IFN-gammaand tumor necrosis factor-related apoptosis-inducing ligand dependent, but not perforin-dependent. Taken together, our results demonstrate that NK1.1+alphabetaTCR+ cell-based immune therapy can inhibit primary tumorigenesis.
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PMID:Alpha-galactosylceramide (KRN7000) suppression of chemical- and oncogene-dependent carcinogenesis. 1286 93

Virus-mediated oncolysis is a rapidly growing field with the potential to dramatically alter the future of cancer therapy. Replication-selective viruses are superior to non-replicating vectors in several aspects, such as the amplification of the initial low-dose viral inoculum up to 10(3)-10(3)-fold, lateralization into neighboring cells, introduction of novel cell killing mechanisms, and a potential for a safe profile. However, due to their capacity to replicate, the importance of tumor selectivity is further underscored. Of the replication-selective viruses, adenoviruses (Ad) possess several attributes that appear essential for targeting and eliminating tumor cells. These include susceptibility to genomic modifications, convergence with cellular pathways implicated in carcinogenesis, and a high oncolytic capacity. A primary tumor targeting strategy of oncolytic Ad is based on re-engineering the viral genome viruses to construct conditionally replicative adenoviruses (CRAds). In this regard, modification of CRAd genome is traditionally designated as type I or type II. Type I CRAds are based on mutation or deletion of early Ad genes. Type II CRAds are based on the placement of essential early Ad genes under tissue/tumor-specific regulatory elements in a heterologous context. Thus, both strategies confer varying degrees of tumor-specific replication. Recent data, however, indicate that type III CRAds, embodying the paradigms of both type I and II, offer better replication selectivity for tumor cells while maintaining efficient oncolysis. These characteristics of CRAds yield therapeutic indices unprecedented heretofore in cancer therapy. However, other biological aspects of CRAds should also be addressed before these agents prove as first-line antitumor agents. When these issues are resolved, novel tumor cell killing potential of CRAds may truly be realized and dramatically alter future cancer therapy.
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PMID:Engineering regulatory elements for conditionally-replicative adeno-viruses. 1287 Oct 22

The clonality of synchronous and metachronous bladder tumors has been studied for years with controversial results. Some recent studies support the 'polyclonal origin' hypothesis, i.e. that independently transformed different tumor cell clones exist in the same bladder cancer patient and arise from the field cancerogenisation affecting the entire bladder urothelium by environmental mutagens. Others could demonstrate a monoclonal origin of primary bladder tumors and its recurrences due to a single genetically transformed cell clone spread through the urinary system. With increasing understanding of the clonal origin of bladder tumors and recurrences, clonality markers might contribute to an early and accurate prediction of tumor recurrence and progression. We used p53 mutations as an identification marker permitting the prediction of clonality in bladder tumors and its recurrences. Primary tumors (n=33) and recurrences (n=63) were screened by direct genomic sequencing the p53 mutation hot spot region, exons 5-8. P53 mutations occurred in 12% in our cohort, predominantly in higher malignant (>or=G2), invasive (>or=T1) tumor samples. We were able to demonstrate intratumoral heterogeneity regarding the p53 status and that recurrences may occur from genetically unrelated primary tumor sites. Some of our results argue for a polyclonal origin of synchronous and metachronous bladder tumors possibly due to the field effect in bladder carcinogenesis. Evidence for a monoclonal origin was found in two cases: one case with a high malignant primary tumor and 3 metachronous recurrences, all of them harbouring the same exon 8 mutation found in the primary tumor; one case with identical mutations of exon 8 in the primary and one recurrent tumor. For further implications concerning clonality of recurrent bladder tumors, p53 status should be combined with a broader range of markers such as CGH and LOH pattern.
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PMID:P53 mutations as an identification marker for the clonal origin of bladder tumors and its recurrences. 1453 39

CD44 has diverse functions in cell-cell and cell-matrix interactions and may be a determinant of metastatic and invasive behaviour in carcinomas. CD44 variant 6 (CD44v6) has been postulated to be involved in both carcinogenesis and tumor progression. Therefore, we have examined CD44v6 expression in tumors from 57 patients with advanced colorectal cancer who received one of two chemotherapy regimes (either irinotecan alone or irinotecan and 5-flurouracil with folinic acid). CD44v6 expression was determined immunohistochemically in 57 paraffin-embedded primary tumor sections and assessed using image analysis software. Strong expression levels of CD44v6 were seen in 24/57 (42%) of tumors, moderate levels in 17/57 (30%), weak levels in 9/57 (16%) and no expression was seen in 7/57 (12%). The pattern of staining was predominantly cytoplasmic, 7/57 tumors also exhibited membrane specific expression. A significant association was found between tumor CD44v6 expression and treatment response (Fisher's exact test p=0.01). Only 1/12 patients with no or weak tumor expression of CD44v6 showed a response to treatment whereas 20/41 (49%) patients with moderate or strong CD44v6 expression responded to treatment. Evaluation of CD44v6 expression of locally advanced and metastatic colorectal tumors may enable the clinician to identify and select patients that will show the best response to irinotecan based chemotherapy.
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PMID:CD44 variant 6 expression predicts response to treatment in advanced colorectal cancer. 1465


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