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PubMed1995

Novel use of a selectable fusion gene as an "in-out" marker for studying genetic loss in mammalian cells.

Recent demonstrations of loss of heterozygosity in a wide variety of human cancers suggest that large multilocus genetic deletions (presumably including tumor suppressor genes) constitute a major class of genetic alteration in human carcinogenesis. Here we show that a bifunctional fusion gene (Hytk), suitable for both positive and negative selection, is an effective marker for studying genetic loss in mammalian cells with minimal interference from point-mutational changes. Studies with a transgenic V79 cell line in which a single functional copy of Hytk was stably inserted into the genome in a retroviral vector showed that loss of the marker (and presumably flanking cellular genetic material) could be induced efficiently by ionizing radiation (gamma-rays and fast neutrons) but only weakly by the powerful point-mutagen benzo[a]pyrene diol epoxide. In a first application of the system, we provide evidence that radiation-induced loss can occur through an indirect mechanism after a high-frequency event. Collectively, our results suggest that the Hytk marker should be a valuable tool for studying genome position effects on the tolerance of genetic loss in cultured human cells that represent different stages in clonal evolution and tumor progression.

3T3 Cells↗
PubMed2003

Preservation of hearing in vestibular schwannomas treated by radiosurgery using Leksell Gamma Knife: preliminary report of a prospective Belgian clinical study.

INTRODUCTION: Radiosurgery is an alternative to the microsurgical resection of vestibular schwannoma (VS). Since its introduction, radiosurgery has been used in more than 8000 patients with VS worldwide and the long term tumor control rates are reported to be 86 to 100%. The aim of this study is to report our experience with Leksell Gamma Knife (LGK) radiosurgery in the management of VS and to evaluate the serviceable hearing preservation rate after one-year follow-up. MATERIAL AND METHODS: Between January 2000 and October 2002, 95 patients with unilateral VS underwent LGK radiosurgery at the University Erasmus Hospital of Brussels with the first worldwide installed LGK C. All patients in our series underwent evaluation with high resolution neurodiagnostic imaging including computed tomography and MRI, and clinical evaluation as well as audiological tests that included tonal and vocal audiometries. The Gardner Robertson (GR) classification is used to report the results of this study. We identified 48 patients treated for VS with LGK, tested and retested with vocal and tonal audiometries by the same team, and followed for a minimum of one year. There were 38 patients with previously untreated VS (9 grade I, 9 grade II, 20 grade III according to Koos) and 10 patients with postoperative evolutive residual tumor. RESULTS: Before LGK, 24 patients had serviceable (17 GR class I and 7 GR class II) hearing; 16 (67%) of these patients had preservation of serviceable hearing (Pure tone average < 50 db and Speech discrimination > 50%) at the one-year audiological follow-up. It was observed that 9 of the 17 GR class I patients (52.9%) maintained their level of audition and 14 of these (82.3%) preserved serviceable hearing. No deterioration of hearing occurred in the 7 patients with preradiosurgery radiosurgery nonserviceable hearing (GR class III) at the one-year follow-up. One patient improved from GR class V to III after LGK. No patient developed trigeminal neuropathy and only one patient who had preradiosurgery facial nerve dysfunction experienced deterioration at one-year follow-up. CONCLUSIONS: In view of the high tumor control rate and excellent long-term cranial nerve preservation rates, LGK radiosurgery should now be considered as an excellent alternative strategy to microsurgery for the management of VS grade I to III as well as in cases of residual tumor after microsurgery. Compared to results obtained in centers with long-term experience, our data suggest that LGK radiosurgery is an efficient reproducible therapeutic approach that offers high rate of hearing preservation. This justifies the choice of radiosurgery as the first treatment option in VS.

Auditory Threshold↗
PubMed2004

Evolution of the exon-intron structure and alternative splicing of the MAGE-A family of cancer/testis antigens.

Cancer/testis antigens (CT-antigens) are proteins that are predominantly expressed in cancer and testis and thus are possible targets for immunotherapy. Most of them form large multigene families. The evolution of the MAGE-A family of CT-antigens is characterized by four processes: (1) gene duplications; (2) duplications of the initial exon; (3) point mutations and short insertions/deletions inactivating splicing sites or creating new sites; and (4) deletions removing sites and creating chimeric exons. All this concerns the genomic regions upstream of the coding region, creating a wide diversity of isoforms with different 5'-untranslated regions. Many of these isoforms are gene-specific and have emerged due to point mutations in alternative and constitutive splicing sites. There are also examples of chimeric mRNAs, likely produced by splicing of read-through transcripts. Since there is consistent use of homologous sites for different genes and no random, indiscriminant use of preexisting cryptic sites, it is likely that most observed isoforms are functional, and do not result from relaxed control in transformed cells.

Alternative Splicing↗
PubMed2003

Quantitative assessment of glioblastoma invasion in vivo.

The aim of this study was the quantitative assessment of the time course and spatial distribution in brain of invading glioblastoma (GBM) cells using a recently described model consisting of RT2 rat GBM cells stably transfected with enhanced green fluorescent protein (eGFP) - called RT2-eGFP - and implanted in Fischer rats. Invasion throughout the brain was verified by confocal microscopy and immunocytochemical staining for eGFP. Rats were sacrificed on post-implantation days 3, 8, and time of death (TOD). First, the entire rat brain was disaggregated at each time point and viable RT2-eGFP cells were counted using flow cytometry with fluorescence as the marker. Next, 2 mm(3) samples of cortex from each of four brain quadrants (bifrontal and bioccipital) were disaggregated at each time point, with tumor cell quantification as before. Tumor cell density, averaged over the entire brain, reached a peak mid-way through its time course, leveling out by TOD. Tumor cell density within bulk tumor (BT) was greatest early in the evolution of the brain tumor, decreasing to its final value mid-way through its time course, due to necrosis. The greatest concentration of tumor cells was within BT, with up to an order of magnitude fewer cells in the periphery, while the number of brain tumor cells invading brain distant from BT remained constant from day 3 until TOD. BT size steadily increased after implantation, with an increasing portion due to central necrosis as time progressed, suggesting that this effect is an important contributor to fatality in this model. Alternatively (or additionally), accumulation of toxins elaborated by tumor cells throughout the brain starting early in the evolution of the tumor may also contribute to fatality.

Animals↗
PubMed2004

The radiographic evolution of radio frequency ablated renal tumors.

PURPOSE: Radio frequency ablation (RFA) of renal tumors is a relatively new technology. Few groups are familiar with the posttreatment appearance of these lesions and how they differ from cryoablated renal masses. We describe the evolution of the appearance of these lesions on followup contrast enhanced (CE) computerized tomography (CT). METHODS AND MATERIALS: A total of 64 consecutive renal tumors treated with RFA from April 2000 to September 2003 for which posttreatment CE-CT was done were included in this study. CE-CT was reviewed at 6 weeks, 3 months, 6 months and every 6 months thereafter to determine the characteristic features and evolution of these lesions. RESULTS: Renal tumors were treated with CT guided percutaneous (34), laparoscopic (28) or open (2) RFA. At a median followup of 13.7 months (range 6 weeks to 29 months) 62 RFA lesions demonstrated an absence of contrast enhancement on CE-CT. Treated endophytic tumors developed a low density, nonenhancing, wedge-shaped defect with fat infiltration seen between the ablated tissue and normal parenchyma. Treated exophytic tumors retained a configuration similar to that of the original with a lack of contrast enhancement and minimal shrinkage. Percutaneous treated lesions developed a peritumor scar or halo that demarcated ablated and nonablated tissue (perirenal fat). Persistent tumor was marked by contrast enhancement within the ablation borders of the original mass in 1 case, whereas tumor recurred after initial successful ablation with an enhancing nodule in 1. CONCLUSIONS: The radiographic features and evolution of radio frequency ablated renal tumors are unique. Successfully treated tumors demonstrated no contrast enhancement, minimal shrinkage and occasional retraction from normal parenchyma by fat infiltration.

Adenocarcinoma, Clear Cell↗
PubMed2006

Evolution and expression of chimeric POTE-actin genes in the human genome.

We previously described a primate-specific gene family, POTE, that is expressed in many cancers but in a limited number of normal organs. The 13 POTE genes are dispersed among eight different chromosomes and evolved by duplications and remodeling of the human genome from an ancestral gene, ANKRD26. Based on sequence similarity, the POTE gene family members can be divided into three groups. By genome database searches, we identified an actin retroposon insertion at the carboxyl terminus of one of the ancestral POTE paralogs. By Northern blot analysis, we identified the expected 7.5-kb POTE-actin chimeric transcript in a breast cancer cell line. The protein encoded by the POTE-actin transcript is predicted to be 120 kDa in size. Using anti-POTE mAbs that recognize the amino-terminal portion of the POTE protein, we detected the 120-kDa POTE-actin fusion protein in breast cancer cell lines known to express the fusion transcript. These data demonstrate that insertion of a retroposon produced an altered functional POTE gene. This example indicates that new functional human genes can evolve by insertion of retroposons.

Actins↗
PubMed2002

p16 and p53 gene alterations and accumulations in the malignant evolution of intraductal papillary-mucinous tumors of the pancreas.

BACKGROUND/PURPOSE: In general, intraductal papillary-mucinous tumors of the pancreas have a favorable prognosis. However, some invasive carcinomas show a rapid progression and a poor prognosis, such as invasive ductal carcinomas of the pancreas. The aim of this study was to clarify the genetic backgrounds underlying the evolution necessary for these tumors to become invasive carcinomas. METHODS: Twenty-three patients with intraductal papillary-mucinous tumors, including 9 adenomas, 5 borderline tumors, 3 noninvasive carcinomas, and 6 invasive carcinomas, along with 24 patients with invasive ductal carcinomas were studied. After microdissection, K- ras mutation and loss of heterozygosity (LOH) of the p16 and p53 genes were investigated. RESULTS: In the intraductal papillary-mucinous tumors, K- ras mutations were frequently seen, without a relationship to histological grade. LOH of the p16 gene was observed increasingly with increasing degrees of histological atypia. LOH of the p53 gene was seen only in invasive carcinomas. The frequency of each genetic alteration in invasive carcinomas was the same as that in invasive ductal carcinomas. The accumulation of genetic alterations was as common in invasive carcinomas, as they were in invasive ductal carcinomas. CONCLUSIONS: The p16 and p53 gene alterations and accumulations observed are crucial events during the carcinogenesis and malignant progression of intraductal papillary-mucinous tumors of the pancreas.

Adenocarcinoma, Mucinous↗
PubMed2004

Alternative approaches for efficient inhibition of hepatitis C virus RNA replication by small interfering RNAs.

Persistent infection with hepatitis C virus (HCV) is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. It has recently been shown that HCV RNA replication is susceptible to small interfering RNAs (siRNAs), but the antiviral activity of siRNAs depends very much on their complementarity to the target sequence. Thus, the high degree of sequence diversity between different HCV genotypes and the rapid evolution of new quasispecies is a major problem in the development of siRNA-based gene therapies. For this study, we developed two alternative strategies to overcome these obstacles. In one approach, we used endoribonuclease-prepared siRNAs (esiRNAs) to simultaneously target multiple sites of the viral genome. We show that esiRNAs directed against various regions of the HCV coding sequence as well as the 5' nontranslated region (5' NTR) efficiently block the replication of subgenomic and genomic HCV replicons. In an alternative approach, we generated pseudotyped retroviruses encoding short hairpin RNAs (shRNAs). A total of 12 shRNAs, most of them targeting highly conserved sequence motifs within the 5' NTR or the early core coding region, were analyzed for their antiviral activities. After the transduction of Huh-7 cells containing a subgenomic HCV replicon, we found that all shRNAs targeting sequences in domain IV or nearby coding sequences blocked viral replication. In contrast, only one of seven shRNAs targeting sequences in domain II or III had a similar degree of antiviral activity, indicating that large sections of the NTRs are resistant to RNA interference. Moreover, we show that naive Huh-7 cells that stably expressed certain 5' NTR-specific shRNAs were largely resistant to a challenge with HCV replicons. These results demonstrate that the retroviral transduction of HCV-specific shRNAs provides a new possibility for antiviral intervention.

Antiviral Agents↗
PubMed1999

Venous and arterial bypass grafts for difficult tumors, aneurysms, and occlusive vascular lesions: evolution of surgical treatment and improved graft results

OBJECTIVE: In the treatment of patients with cranial base tumors, unclippable aneurysms, or medically intractable ischemia, it may be necessary to use high-flow bypass grafts. The indications, surgical techniques and complications are discussed. METHODS: During a 10-year period, 99 saphenous vein grafts and 3 radial artery grafts were performed for 101 patients, i.e., 72 with neoplasms, 23 with aneurysms, and 6 with ischemia. Clinical follow-up monitoring of the patients was by direct examination or telephone interview, with a mean follow-up period of 41.2 months (range, 5-147 mo). Radiological follow-up monitoring was by magnetic resonance imaging, magnetic resonance angiography, or three-dimensional computed tomographic angiography, with a mean follow-up period of 32 months (range, 1-120 mo). During the follow-up period, there was one late graft occlusion and one graft stenosis. RESULTS: The use of intraoperative angiography improved the patency rate from 90 to 98% and reduced the incidence of perioperative stroke from 13 to 9.5%. Ninety-two percent of the patients were in excellent or good neurological condition at the time of discharge from the hospital, compared with 95% before surgery. The perioperative mortality rate was 2%. Other complications included three intracranial hematomas, rupture of a vein graft in a patient with Marfan's syndrome, and five tumor resection-related problems. The long-term survival rates for patients who received grafts were excellent for patients with benign tumors, fair to poor for patients with malignant tumors, good for patients with aneurysms, and excellent for patients with ischemia. CONCLUSION: The results of saphenous vein and radial artery grafting have been greatly improved by the use of intraoperative angiography, improvements in surgical techniques, and improved perioperative treatment.

Journal Article↗
PubMed1990

Invasion of human brain tumors in vitro: relationship to clinical evolution.

Embryonic chick heart fragments were confronted in vitro with cells from 26 freshly resected human brain tumors. The tumor-derived cells were scored according to their survival and invasiveness. Four different responses were observed: disintegration of the tumor-derived cells (Type I); survival of cells without progressive engulfing or invasion of the heart fragment (Type II); initial encircling of the heart fragment followed by invasion (Type III); and massive invasion on initial contact (Type IV). Pattern Type III or IV was seen in 11 of 14 preparations derived from malignant tumors, and pattern Type I or II was seen in seven of 10 preparations derived from benign tumors. These results suggested that "classical malignancy," based upon the histological classification and the degree of spread in vivo, correlated with invasiveness in vitro.

Animals↗
PubMed2001

Head and neck squamous cell carcinoma in elderly patients: a long-term retrospective review of 273 cases.

BACKGROUND: The prolongation of life expectancy results in an increasing number of malignant neoplasms occurring in the elderly population. For a long time these patients were not considered good candidates to receive aggressive therapy and probably were inadequately treated in many instances. OBJECTIVE: To assess the outcome of patients older than 74 years who had had head and neck squamous cell carcinoma. MATERIALS AND METHODS: In our database of 4610 consecutive patients with head and neck squamous cell carcinomas who were evaluated and treated at the Centre Oscar Lambret, Northern France Comprehensive Cancer Center, Lille, over a 10-year period (1974-1983), we identified 273 patients who were 75 years or older. The outcome was updated for all patients included in the database. RESULTS: A significantly higher proportion of females were noted in the older patient group (43/273, 15.8%) than in younger patient group (192/4337, 4.4%, P<.001). There were no differences for primary site except for hypopharyngeal squamous cell carcinoma that occurred less frequently in the elderly patients (8.8% vs 14.5%, borderline significance P =.02). There were no differences for TNM stage grouping, histological classification, incidences of previous cancer, and comorbidities. Surgery was performed in a smaller proportion of older patients (13.9% vs 27.4%, P<.001, for the primary site and 15.4% vs 35.6%, P<.001, for those occurring in the neck) as well as chemotherapy that was delivered in 5.5% vs 17.7% (P<.001). On the contrary, there was no difference in radiotherapeutic treatments. Tolerance to treatment was similar and there was the same proportion of persistent diseases 2 months after completion of the overall treatment (27.8% vs 25.4%, P =.94). Pooling local, regional, and distant failures and metachronous cancers, there was a borderline lower incidence in older patients (57.1% vs 64.2%, P =.02), which is explained by an obvious shorter life expectancy. If survival is not meaningful in such a comparison (5-year survival 23.8% vs 36.4%), then the causes of deaths may be compared. Among the 4067 patients who were dead at the last update, index tumor evolution-related deaths numbered 130 (48.1% of dead patients in this cohort) in older patients compared with 2045 (53.9% of dead patients in this cohort), which was not significantly different. There was no difference in treatment-related deaths (11.1% vs 9.3%). Fewer intercurrent disease-related deaths occurred in the older patients (19.7% vs 11.8%). CONCLUSIONS: Head and neck squamous cell carcinoma in elderly patients did not seem to have a significantly different outcome when compared with head and neck squamous cell carcinoma occurring in younger patients. When properly monitored, conventional therapies seem feasible in older patients.

Adolescent↗
PubMed1983

The relationship between family history, exposure to exogenous hormones, and estrogen receptor protein in breast cancer.

Eight-hundred and thirteen patients were prospectively studied to examine the influence of family history and the prior use of exogenous hormones as covariables in the subsequent expression of estrogen receptor protein (ERP) in the primary tumor of patients with breast cancer. Cases were divided by menstrual status; there were 385 pre- and perimenopausal and 428 postmenopausal patients. The influence of prior exposure to estrogen replacement therapy (ERT) in postmenopausal patients or oral contraceptives (OC) in pre- and perimenopausal patients on tumor ERP was analyzed controlling for family history: none, first degree (1 degree, mother or sister), second degree (2 degrees, grandmother or aunt), or both 1 degree and 2 degrees relatives. The results showed no influence of the prior use of ERT in postmenopausal women on subsequent tumor ERP. Among pre- and perimenopausal women, those with a family history of breast cancer in only a 1 degree relative, showed a borderline significant association between prior OC usage and subsequent tumor ERP. The use of OC was consistently associated with ERP negative tumors (9/9) whereas of 29 patients who had no prior OC exposure 17 had ERP negative tumors (P = 0.04, Fisher's Exact Test). Analysis of the prior exposure to OC, verified with the primary care physician or pharmacist, showed that these patients first used OC at the mean age of 32.2 years, had used OC for a mean duration of 41.9 months and stopped OC use a mean of 79.5 months before being diagnosed as having breast cancer. These results suggest that in a subset of patients with breast cancer, and a first degree relative only who had breast cancer, prior exposure to OC may influence the subsequent ERP status of the tumor. This is not due to exogenous estrogen saturation of receptors as there was a long latent period between exposure and diagnosis. Alternative hypotheses as to the mechanism of selection of subsequent tumor ERP may be either inhibition of ERP positive preneoplastic or tumor cell clones early in the evolution of the tumor or early selection of a tumor capable of endogenous estrogen synthesis with receptor saturation.

Breast Neoplasms↗
PubMed2000

Actin depolymerization and polymerization are required during apoptosis in endothelial cells.

In order to understand the role of actin microfilaments in the apoptotic process, we followed their evolution during tumor necrosis factor-alpha (TNF)-induced apoptosis in bovine aortic endothelial (BAE) cells. Using Western blotting analysis and immunofluorescence microscopy, we observed that the actin microfilaments network was disrupted in apoptotic cells. Depolymerization of F-actin was concomitant with internucleosomal DNA degradation and with the morphological changes associated with apoptotic cell death. However, using the actin microfilament disrupting agent, cytochalasin, we present evidence that the formation of blebs leading to apoptotic cell fragmentation requires neopolymerization of actin. Indeed, in the presence of cyochalasin, induction of apoptosis (internucleosomal DNA degradation) in BAE cells by TNF and cycloheximide was not associated with these classical morphological markers of apoptosis. Moreover, when added to BAE cells showing incipient apoptotic fragmentation, cytochalasin E reversed this process. We also observed an accumulation of actin at the basis of the apoptotic bodies in formation in these cells. Together, these results suggest that the actin network of flattened cells is disrupted concomitantly to the morphological modifications associated to the apoptotic cell death, and that the cytochalasin-sensitive reorganisation of actin is required to the formation of apoptotic blebs.

Actins↗
PubMed2004

Frequency of HLA-C alleles in differentiated thyroid carcinoma in southeastern Spain.

BACKGROUND: The development of thyroid carcinoma may be influenced genetically and has been associated with certain HLA alleles. HLA-C alleles have not been studied in depth, because available serology techniques have not been very reliable in detecting them. However, the development of molecular biology provided an efficient and reliable technique for allele detection. The aims of the current study were to determine whether there is a significant association between any HLA-C allele and differentiated thyroid carcinoma and to establish the possible susceptibility or protection alleles related to these tumors. METHODS: HLA-C genotyping was performed in 63 patients undergoing surgery for differentiated thyroid carcinoma (57 patients with the papillary subtype and 6 patients with the follicular subtype). A representative sample of 100 nonrelated healthy Caucasians was used as a control group from the same geographic area. The polymerase chain reaction-sequence-specific primer technique was used for HLA-C genotyping. The clinical variables analyzed were age, gender, family history of thyroid pathology, residence in areas of endemic goiter, asymptomatic status, presence of hyperthyroidism, compressive symptoms, presence of an intrathoracic thyroid component, histologic variables of the tumor, and evolution. The chi-square test, the Mantel-Haenszel test, and the Bonferroni correction were used for the statistical analysis. RESULTS: In the control group, a significant correlation was observed between the lower frequency of the HLA-Cw7 allele and the development of differentiated thyroid carcinoma (P < 0.05). Analysis of the different clinical variables revealed a relation between HLA-C alleles and three clinical situations: cervical lymph node involvement with HLA-Cw7 and HLA-Cw2, vascular involvement with HLA-Cw7 and HLA-Cw1, and cervical carcinoma recurrence with HLA-Cw1. However, after application of the Bonferroni correction, only the association between HLA-Cw7 and lymphatic (P(c) = 0.0483) or vascular involvement (P(c) = 0.0324) persisted. CONCLUSIONS: The results revealed a relation between HLA-Cw7 and differentiated thyroid carcinoma. In future investigations, HLA-C typing may help to identify patients with a poor prognosis.

Adult↗
PubMedDate not supplied

Massive blastic infiltration of the liver: a cause of fulminant hepatic failure.

The clinical and pathological findings in four cases of fulminant hepatic failure due to massive infiltration of the liver by acute leukemia or lymphoma are reported. Liver abnormalities were found simultaneously with or led to the discovery of hematologic malignancies, and consisted of marked hepatomegaly and severe hepatocellular insufficiency associated with hyperlactatemia. The blood malignancies were peculiar in their fast cellular growth and large tumor mass. Evolution was rapidly fatal in all these cases. In another patient, marked hepatomegaly and hyperlactatemia revealed the presence of a widespread lymphoma before the appearance of hepatocellular insufficiency. Immediate chemotherapy was instituted, and complete remission without hepatic complication was obtained. It is suggested that malignant hematological diseases with fast cellular growth may present as fulminant hepatic failure. In order to avoid a rapidly fatal outcome secondary to liver failure and metabolic disorders, early recognition of these malignancies is necessary so as to assure prompt administration of appropriate chemotherapy.

Autopsy↗
PubMed1991

Phosphorylation of brain (Na+,K+)-ATPase alpha catalytic subunits in normal and epileptic cerebral cortex: II. Partial seizures in human epilepsy.

We examined the activity and phosphorylation level of (Na+,K+)-ATPase (E.C. 3.6.1.3) partially purified from normal and epileptic human cortices. Control patients (n = 11) were operated on for a non-epileptogenic deep brain lesion, while epileptic patients (n = 10) were operated on for temporal or frontal originating partial seizures, resistant to medications or secondary to evolutive brain tumors. No differences in the specific activity of microsomal (Na+,K+)-ATPase were observed between the two groups of patients. After partial purification of the enzyme followed by SDS-polyacrylamide gel electrophoresis, (Na+,K+)-ATPase catalytic subunit had a decreased affinity for K+ in human epileptic cortex and lost its sensitivity to phenytoin dephosphorylation. Indirect evidence suggests that those abnormalities of (Na+,K+)-ATPase in human epileptic cortex hold preferentially true for the alpha(-) enzymatic subunit. Those results indicate that, in human epileptic cortex, (Na+,K+)-ATPase and most probably its glial subtype is altered in its K+ regulation and phenytoin sensitivity and could be responsible for ictal transformation and seizure spread.

Brain↗
PubMed2026

Differences between mitotically old and young endometrial tumors.

Human tumors likely differ in their mitotic ages, reflecting how many divisions elapse between the final tumor progenitor cell and surgical removal. We used a rapidly fluctuating CpG (fCpG) methylation clock to infer relative endometrial adenocarcinomas (EAC) mitotic ages. Experimentally, young tumors initiated from single cells show low-diversity, high-variance fCpG distributions with trimodal peaks near 0%, 50%, and 100%, reflecting inherited progenitor methylation states. fCpG methylation becomes polymorphic with divisions, and older tumors exhibit higher diversity, lower variance, and unimodal distributions centered around 50%. Mitotic ages varied across EAC samples. Synchronous hyperplasia and invasive regions generally shared similar ages, and primary-metastatic EAC pairs showed both synchronous and stepwise progression. The Cancer Genome Atlas (TCGA) EACs also showed variable mitotic ages: younger tumors were enriched for proliferation pathways, whereas older tumors showed more immune infiltration, immune-pathway activation, and evidence of T-cell exhaustion. These results show that human tumors can be ranked by mitotic age and suggest that the growth of older cancers is restrained by immune surveillance. &#xa9; 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Humans↗
PubMed1993

Genetic and molecular basis for cellular senescence.

Normal human and rodent cells in culture exhibit a finite life span at the end of which they exhibit morphological changes and cease proliferating, a process termed cellular senescence or cellular aging. Many cancer cells differ from normal cells in that they do not senesce and have an indefinite life span in culture, suggesting that alterations relating to cellular senescence are involved in the neoplastic evolution of tumor cells. Recent experimental results strongly support a genetic basis for cellular senescence. Defects in the senescence program in transformed cells can be corrected by introduction of a specific chromosome from normal cells into the abnormal cells. Using this approach, possible senescence genes have been mapped to specific chromosomes. Cell cycle control genes that regulate entry into the DNA synthetic phase of the cell cycle must be altered in senescent cells. Recent findings suggest that phosphorylation of the retinoblastoma gene is altered in senescent cells. It is possible, but not yet proven, that aging at the cellular level contributes to the aging of the individual. Therefore, an understanding of cellular senescence at the genetic and molecular levels may provide new insights into both the cancer and aging processes.

Animals↗