Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Squamous epithelial dysplasia is often observed multifocally in the cancerous oesophagus and is presumably considered to be a pre-cancerous lesion. A mutation of the p53 tumour suppressor gene is commonly identified in oesophageal cancer and dysplasia. p53 mutations can be anticipated immunohistochemically. In order to confirm the biological and clinical significance of p53 expressions in oesophageal field carcinogenesis, immunostaining for p53 in cancerous and multifocal precancerous lesions from resected human oesophagus was systematically investigated, while paying special attention to the contiguity of these lesions. Lesions expressing p53 were detected in 46.5% (20 of 43 lesions) of the invasive carcinoma, and in 51.0% (46 of 90 lesions) of the carcinoma in situ, and in 51.4% (92 of 179 lesions) of the dysplasia. Next, the p53 expression in dysplasia was compared with that in carcinoma for the same case. 37 of 39 (94.8%) dysplasias contiguous to p53-positive carcinomas also expressed p53 (P<0.0001). On the other hand, the isolated dysplasias without contiguity to p53-positive carcinomas, only expressed p53 protein in 44.0% (11 of 25 lesions). No significant correlations were found between the p53 staining and either the clinicopathological features or prognosis. Discordant p53 alterations, such as those seen in cancerous and isolated precancerous lesions, may thus demonstrate further evidence for a multicentric or field carcinogenesis of the human oesophagus.
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PMID:p53 expression in squamous dysplasia associated with carcinoma of the oesophagus: evidence for field carcinogenesis. 1099 51

The optimal approach to upper tract TCC remains to be redefined. A routine nephroureterectomy for every filling defect in the upper urinary system, even in the case of a normal contralateral kidney, constitutes an unnecessary mutilation in more than two thirds of the cases. Nephroureterectomy does not reduce the need for a long-term cystoscopic follow-up because of the high rate of bladder tumor recurrence that may happen years later after nephroureterectomy. Relying solely on radiography and cytology, lacking sensitivity and specificity, to recommend a nephroureterectomy is against the principles of oncologic surgery, especially now that preoperative histologic proof is easy to obtain endoscopically without compromising cancer control. Ureteroscopy, rigid and flexible, provides a complete assessment of the upper urinary system. Biopsy specimens taken with ureteroscopy may be sufficient for grading but less adequate for staging of the tumor. The authors reserve ureteroscopy for ureteral tumors and small (< 1.5 cm) single tumors of the renal pelvis. They approach large or multiple tumors of the renal pelvis percutaneously, in which a full histologic assessment is possible along with a complete resection of the tumor. The decision on the therapeutic approach is made only after the final pathologic report is reviewed. Grade I and grade II superficial disease (Ta, T1) can be treated endoscopically with minimal morbidity and with an efficiency comparable with the standard more invasive nephroureterectomy (Table 5). The indications for endourologic treatment in these cases can be extended safely beyond a solitary kidney or a high surgical risk to include any healthy individual with a normal contralateral kidney who is willing to commit to a rigorous lifelong follow-up. Patients with grade II T1 lesions require a more vigilant follow-up. For grade III Ta disease, more caution should be exercised in selecting these patients for elective endourologic management. When criteria of good prognosis are found, such as absence of carcinoma in situ, presence of diploidy, low p53 expression and a single-tumor, endoscopic management can be offered [table: see text] with a closer follow-up and resorting always to immediate nephroureterectomy at the first evidence of upstaging. Because of the high incidence of recurrence and progression, elective endourologic management for grade III T1 tumors is not recommended. Endoscopic conservative surgery still can be offered in the cases of a solitary kidney or chronic renal insufficiency or for poor surgical candidates. Patients with localized stages (T2, T3) TCC should be offered immediate nephroureterectomy. The authors do not expect adequate endoscopic extirpation with muscle invasive tumors. Although the tissue removed may include deep layers, deep resection is precluded by the thin renal pelvic wall and the associated risk for perforation. Patients with more extensive disease (T3, T4) have a bad prognosis regardless of the form of therapy. Achieving local control percutaneously while preserving as many nephrons as possible for the future chemotherapy can be a reasonable option.
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PMID:Primary percutaneous approach to upper urinary tract transitional cell carcinoma. 1109 71

The molecular genetic changes reported in bladder tumors can be classified as primary and secondary aberrations. Primary molecular alterations may be defined as those directly related to the genesis of cancer. These are frequently found as the sole abnormality and are often associated with particular tumors. There are characteristic primary abnormalities involved in th production of low-grade/well-differentiated neoplasms, which destabilize cellular proliferation but have little effect on cellula "social" interactions or differentiation, as well as the rate of cell death or apoptosis. Other molecular events lead to high-grad neoplasms which disrupt growth control, including the cell cycle and apoptosis, and which have a major impact on biological behavior. A primary target leading to low-grade papillary superficial bladder tumors resides on chromosome 9, while p53 gene alterations are commonly seen in flat carcinoma in situ. Other molecular alterations must be elucidated, as many non-invasive neoplasms have neither chromosome 9 nor p53 alterations. Novel approaches utilizing tissue microdissection techniques an molecular genetic assays are needed to shed further light on this subject. Secondary genetic or epigenetic abnormalities may be fortuitous, or may determine the biological behavior of the tumor. Multiple molecular abnormalities are identified in most human cancers studied, including bladder neoplasms. The accumulation, rather than the order, of these genetic alterations may be the critical factor that grants synergistic activity. In this regard, it is noteworthy that many of the genes that are altered act upon the two recognized critical growth and senescenc pathways, TP53 and RB. These particular molecular aberrations may be especially important to evaluate for their use in the management of bladder cancer because of their commonality in progressive forms of the disease. Thus, clinical trials are underway to explore their use in specific situations, particularly in the surgical management of locally advanced disease, and to determine whether adjuvant chemotherapy in such patients may be of benefit. The use of molecular alterations in the management of non-invasive bladder neoplasms remains to be firmly established. Our knowledge of molecular alterations important in bladder cancer progression is far from complete, and further study is necessary to further elucidate cruci pathways involved in progression and therapeutic response. As per preneoplastic conditions, difficulties in identifying and interpreting the significance of phenotypic changes have imposed certain limitations, as has an evolving nomenclature and issues of reproducibility in interpreting morphologica criteria. Nevertheless, molecular alterations involving chromosome 9q and the INK4A locus in papillary superficial tumors vs changes in chromosomes 14q and 8q, p53 and RB in flat carcinoma in situ lesions may indicate a molecular basis for early events that lead to varying pathways in urothelial tumorigenesis. Studies aimed at revealing the clinical relevance of genet instability, as well as molecular or epigenetic alterations, in urothelium and preneoplastic lesions of otherwise morphologicall normal appearance are needed to further advance knowledge in the field. Clinical advances in bladder cancer will be facilitated by novel animal models paralleling the human disease. Molecular diagnostics, particularly specific antigen expression, fluorescence in situ hybridization and microsatellite analyses, have show great promise as screening and follow-up methodologies, and may supplement urine cytology in the diagnosis and characterization of new and recurrent disease. In addition, the use of high-throughput genomic/proteomic assays, linked to comprehensive databases, and coupled with robust bioinformatics will be key elements in elucidating the components of regulatory and signaling pathways involved in bladder tumorigenesis and cancer progression.
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PMID:Genetic and molecular markers of urothelial premalignancy and malignancy. 1114 7

The aim of this study was to identify the pattern and significance of expression of p53 and PCNA in cholangiocarcinoma and primary sclerosing cholangitis. Histological sections from 18 patients with cholangiocarcinoma (3 of the cases were associated with primary sclerosing cholangitis), 10 patients with primary sclerosing cholangitis without cholangiocarcinoma, and 7 patients with cirrhosis without cholangiocarcinoma or primary sclerosing cholangitis were stained immunohistochemically for p53 and PCNA. Samples from 17 patients with cholangiocarcinoma (94%) stained positively for p53. Among these 17 cases, nontumorous bile duct epithelium was positive in 7 (including 3 cases with primary sclerosing cholangitis and 2 with carcinoma in situ), and were positive proliferating bile ductules in 4 cases. The single p53-negative cholangiocarcinoma did not show p53 positivity in either the bile duct epithelium or the proliferating bile ductules. Bile ductal and ductular cells in all 10 patients with primary sclerosing cholangitis without cholangiocarcinoma and in the 7 controls were not reactive for p53. All 18 samples from patients with cholangiocarcinoma (100%) were positive for PCNA protein. Bile duct epithelium was positive for PCNA in nine cases (90%) of primary sclerosing cholangitis without cholangiocarcinoma and in six (85%) controls. Our study showed a high rate of p53 expression (94%) in cholangiocarcinoma. The adjacent uninvolved bile duct epithelium was also immunoreactive for p53 in 7 of 17 patients (41%). These findings suggest an early p53 mutation in bile ductal cells in cholangiocarcinogenesis. Expression of p53 may potentially be used to identify or screen, by bile duct brushings, cases of primary sclerosing cholangitis suspected of harboring cholangiocarcinoma. Expression of PCNA was a universal feature in cholangiocarcinoma.
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PMID:Expression of p53 and PCNA in cholangiocarcinoma and primary sclerosing cholangitis. 1114 21

Laryngeal squamous-cell carcinoma is often preceded by pre-malignant lesions. In this study, pre-malignant as well as malignant laryngeal lesions were analyzed using p53 immunohistochemistry and in situ hybridization for chromosomes 1, 7, 9, 17 and 18. Microsatellite analysis was performed on laser-microdissected tissue fragments with the aim of studying loss of heterozygosity (LOH) of 9p21, 17p13 and 18q21. Sequential biopsies were analyzed from a few cases to study genetic progression in more detail. The following genetic progression patterns were observed: (i) histologically normal mucosa and hyperplastic lesions without malignant progression were typically disomic for all chromosomes tested and showed no or only basal cell layer positivity for p53 and no allelic loss; (ii) hyperplastic lesions preceding dysplastic/invasive growth frequently showed trisomy for chromosome 7 and LOH of 9p21 and 17p13, and small foci within these lesions sometimes showed tetraploidization and p53 positivity; (iii) dysplastic lesions were characterized by a tetraploid chromosome content, LOH of 9p21 and 17p13 and p53 positivity; (iv) carcinoma in situ lesions and invasive laryngeal carcinomas showed a more unbalanced chromosome pattern and an additional 18q21 LOH. These results show that different steps in aneuploidization correlate with LOH of 9p21, 17p13 and 18q21 in early laryngeal carcinogenesis. These genomic changes could be of potential use in the diagnosis and prognosis of pre-malignant laryngeal lesions.
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PMID:Specific steps in aneuploidization correlate with loss of heterozygosity of 9p21, 17p13 and 18q21 in the progression of pre-malignant laryngeal lesions. 1114 44

The MCF10AT premalignant human breast epithelial cells form benign ductal structures in immunodeficient mice which sporadically progress to carcinoma in situ and invasive cancers of different histologic types. MCF10CA1 cell lines are malignant variants derived by serially passing small pieces of tumors in athymic mice before establishing cells in culture. As these MCF10CA1 variants gave rise to heterogeneous tumors, some cell lines were cloned. Inoculated into immunodeficient mice, these variants produce squamous carcinomas with an undifferentiated component or adenocarcinomas also with an undifferentiated component. Immunohistochemistry utilized antibodies against DF3, c-erbB-2, cyclin Dl, m keratin, p keratin, p53, B72.3 and estrogen receptor. We detected characteristic patterns for squamous carcinomas, for adenocarcinomas, and for each undifferentiated component, that is the undifferentiated components of the squamous and glandular carcinomas were distinct. Only adenocarcinomas were focally ER positive. One uncloned variant that produced cancers with a glandular component, MCF10CA1h, was cloned and cells were injected into mice. This clone produced only undifferentiated carcinomas that, compared to tumors formed by the parental uncloned variant, had lost ER, DF3 and c-erbB-2 expression, but more strongly expressed p53. Our data demonstrate the potential of the premalignant MCF10AT model to generate heterogeneity, including both estrogen receptor-positive as well as estrogen receptor-negative tumors, during progression.
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PMID:Progression of premalignant MCF10AT generates heterogeneous malignant variants with characteristic histologic types and immunohistochemical markers. 1120 Jul 73

To investigate tumorigenesis in the gastric hyperplastic polyp (HP), we evaluated 19 HPs with and 50 HPs without dysplasia (including carcinoma in situ), as compared with normal mucosa and fundic gland polyps. Helicobacter pylori density was highest in HPs without dysplasia. Apoptotic activity and Ki-67 and p53 expression also were higher in dysplasia in HPs than in normal mucosa, fundic gland polyps, or HPs themselves. The p21WAF1/CIP1 and cyclin D1 levels, in contrast, were highest in HPs. In HPs without dysplasia, size was correlated positively with the degree of stromal inflammation and with p53 and cyclin D1 expression. p53 and c-Ki-ras mutations were detected in 41% (8/19) and 5% (1/19) of dysplasia (including carcinoma in situ) in HPs. Our results demonstrate that the HP enlarges with enhanced cell turnover and overexpression of p53, p21WAF1/CIP1, and cyclin D1, associated with H pylori-related inflammation, and that p53 but not c-Ki-ras mutations may have an important role in dysplastic change in HPs.
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PMID:p53, but not c-Ki-ras, mutation and down-regulation of p21WAF1/CIP1 and cyclin D1 are associated with malignant transformation in gastric hyperplastic polyps. 1178 22

Molecular and kinetic analyses have contributed to our understanding of the biology of transitional cell carcinomas (TCC) of the bladder. The concordant pattern of X-chromosome inactivation of multiple TCCs appearing at different times and at different sites and concordant genetic abnormalities in a subset of muscle-invasive TCC strongly support a monoclonal origin and a homogeneous tumor cell selection throughout the neoplasm. However, topographic intratumor heterogeneity results from the accumulation of genetic lesions in tumor suppressor genes, predominantly neurofibromatosis (NF)-1-defective in the superficial compartment and tumor protein p53 (TP53)-defective in the deep one, with lower proliferation and down-regulation of apoptosis in the latter. TCCs follow the general concept of multistep carcinogenesis and proceed through two distinct genetic pathways responsible for generating different TCC morphologies. These are the inactivation of cyclin-dependent kinase inhibitors (p15, p16, and p21WAF/CIP1) in low-grade TCC and early TP53-mediated abnormalities in high-grade TCC. TCC progression correlates with genetic instability and accumulation of collaborative genetic lesions mainly involving TP53, retinoblastoma (RB)-1, and growth factors. Distinctive genetic (low incidence of RB-1 and NF-1 abnormalities) and kinetic (slower cell turnover) profiles also correlate with a "single-file" infiltration pattern and poor survival in muscle-invasive TCCs. The underlying molecular changes of carcinoma in situ involve multiple and more extensive deletions (normally TP53-defective) than coexistent invasive TCC, suggesting an independent genetic evolution, while low-grade dysplasia is mainly polyclonal and shows a low rate of gene deletions.
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PMID:Molecular and kinetic features of transitional cell carcinomas of the bladder: biological and clinical implications. 1131 26

Urothelial tumors develop along two distinctive phenotypic pathways (superficial papillary non-invasive tumors versus flat carcinoma in situ lesions), with markedly different biological behavior and prognosis. Although multiple genetic alterations have been identified in human bladder cancer, their cause-effect relationship with the two pathways has not been firmly established. Using a urothelium-specific promoter of the uroplakin II gene, we showed earlier in transgenic mice that the urothelial expression of SV40T antigen, which inactivates p53 and pRb, induced carcinoma in situ and invasive and metastatic bladder cancer. In striking contrast, we demonstrate here that the urothelial expression of an activated Ha-ras in transgenic mice caused urothelial hyperplasia and superficial papillary non-invasive bladder tumors. These results provide strong, direct experimental evidence that the two phenotypical pathways of bladder tumorigenesis are caused by distinctive genetic defects. Our results indicate that Ha-ras activation can induce urothelial proliferation in vivo; and that urothelial hyperplasia is a precursor of low-grade, superficial papillary bladder tumors. Our transgenic models provide unique opportunities to study the detailed molecular events underlying different types of bladder neoplasms, and can serve as useful preclinical models for evaluating the in vivo efficacy of preventive and therapeutic agents that act on various signaling pathways in bladder cancer.
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PMID:Role of Ha-ras activation in superficial papillary pathway of urothelial tumor formation. 1136 Jan 81

A precancerous change has been identified incidentally in resected specimens from patients who have undergone cholecystectomy. We focused on chronic cholecystitis, showing a thick and sclerotic wall caused by recurrent inflammation, e.g. contracted cholecystitis, and examined the malignant potential of these lesions. We studied 88 patients who had undergone cholecystectomy. Contracted cholecystitis was diagnosed, using our criteria, in 28 of these cases. Ordinary chronic cholecystitis was diagnosed in 50 cases and gallbladder carcinoma in ten cases. We examined the expression of p53, Ki-67, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) immunohistochemically. Severe dysplasia or carcinoma in situ in a very small portion of the specimen was identified with hematoxylin-eosin staining in four cases (14.3%) of contracted cholecystitis. These specimens revealed a positive expression of not only p53, but also Ki-67, iNOS, and COX-2. Statistical significance was shown among the three disease groups in terms of the incidence of p53 overexpression, respectively (P<0.05). The results of this study suggest that contracted cholecystitis could be an early change leading to carcinogenesis.
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PMID:Significance of contracted cholecystitis lesions as high risk for gallbladder carcinogenesis. 1141 Mar 19


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