55 research outputs found
Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model
AbstractSmall cell lung cancer (SCLC) is a highly aggressive human tumor with a more than 95% mortality rate. Its ontogeny and molecular pathogenesis remains poorly understood. We established a mouse model for neuroendocrine (NE) lung tumors by conditional inactivation of Rb1 and Trp53 in mouse lung epithelial cells. Mice carrying conditional alleles for both Rb1 and Trp53 developed with high incidence aggressive lung tumors with striking morphologic and immunophenotypic similarities to SCLC. Most of these tumors, which we designate MSCLC (murine small cell lung carcinoma), diffusely spread through the lung and gave rise to extrapulmonary metastases. In our model, inactivation of both Rb1 and p53 was a prerequisite for the pathogenesis of SCLC
Primary Leiomyosarcoma of the Adrenal Gland
We report a rare case of a primary leiomyosarcoma of the adrenal gland. A 73-year-old woman presented with an inferior
vena cava syndrome. MR imaging was suggestive of a large tumour originating from the right adrenal gland. Angiography
revealed a tumour vascularised by the right adrenal artery. At explorative laparotomy a tumour of 27 cm in diameter was
found which was completely fixed to the liver; the tumour was therefore considered unresectable. As a consequence of the
mechanical problems caused by this large tumour, the patient died 3 weeks after the operation. Autopsy revealed no distant
metastases or other primary tumour site
Keratinocyte sonic hedgehog up-regulation drives the development of giant congenital nevi via paracrine endothelin-1 secretion
Giant congenital nevi are associated with clinical complications such as neurocutaneous melanosis and melanoma. Virtually nothing is known about why some individuals develop these lesions. We previously identified the sonic hedgehog (Shh) pathway regulator Cdon as a candidate nevus modifier gene. Here we validate this by studying Cdon knockout mice, and go on to establishing the mechanism by which Shh exacerbates nevogenesis. Cdon knockout mice develop blue nevi without the need for somatic melanocyte oncogenic mutation. In a mouse model carrying melanocyte NRAS, we found that strain backgrounds that carry genetic variants that cause increased keratinocyte Shh pathway activity, as measured by Gli1 and Gli2 expression, develop giant congenital nevi. Shh components are also active adjacent to human congenital nevi. Mechanistically, this exacerbation of nevogenesis is driven via the release of the melanocyte mitogen endothelin-1 from keratinocytes. We then suppressed nevus development in mice using Shh and endothelin antagonists. Our work suggests an aspect of nevus development whereby keratinocyte cytokines such as endothelin-1 can exacerbate nevogenesis, and provides potential therapeutic approaches for giant congenital nevi. Furthermore, it highlights the notion that germline genetic variation, in addition to somatic melanocyte mutation, can strongly influence the histopathological features of melanocytic nevi
Differential loss of chromosome 11q in familial and sporadic parasympathetic paragangliomas detected by comparative genomic hybridization
Parasympathetic paragangliomas (PGLs) represent neuroendocrine tumors
arising from chief cells in branchiomeric and intravagal paraganglia,
which share several histological features with their sympathetic
counterpart sympathoadrenal paragangliomas. In recent years, genetic
analyses of the familial form of PGL have attracted considerable interest.
However, the majority of paragangliomas occurs sporadically and it remains
to be determined whether the pathogenesis of sporadic paraganglioma
resembles that of the familial form. Furthermore, data on comparative
genetic aberrations are scarce. To provide fundamental cytogenetic data on
sporadic and hereditary PGLs, we performed comparative genomic
hybridization using directly fluorochrome-conjugated DNA extracted from 12
frozen and 4 paraffin-embedded tumors. The comparative genomic
hybridization data were extended by loss of heterozygosity analysis of
chromosome 11q. DNA copy number changes were found in 10 (63%) of 16
tumors. The most frequent chromosomal imbalance involved loss of
chromosome 11. Six of seven familial tumors and two of nine sporadic
tumors showed loss of 11q (86% versus 22%, P = 0.012). Deletions of 11p
and 5p were found in two of nine sporadic tumors. We conclude that overall
DNA copy number changes are infrequent in PGLs compared to sympathetic
paragangliomas and that loss of chromosome 11 may be an important event in
their tumorigenesis, particularly in familial paragangliomas
Losses of chromosomes 1p and 3q are early genetic events in the development of sporadic pheochromocytomas
Despite several loss of heterozygosity studies, a comprehensive genomic
survey of pheochromocytomas is still lacking. To identify DNA copy number
changes which might be important in tumor development and progression and
which may have diagnostic utility, we evaluated genetic aberrations in 29
sporadic adrenal and extra-adrenal pheochromocytomas (19 clinically benign
tumors and 10 malignant lesions). Comparative genomic hybridization was
performed using directly fluorochrome-conjugated DNA extracted from frozen
(16) and paraffin-embedded (13) tumor tissues. The most frequently
observed changes were losses of chromosomes 1p11-p32 (86%), 3q (52%), 6q
(34%), 3p, 17p (31% each), 11q (28%), and gains of chromosomes 9q (38%)
and 17q (31%). No amplification was identified and no difference between
adrenal and extra-adrenal tumors was detected. Progression to malignant
tumors was strongly associated with deletions of chromosome 6q (60% versus
21% in clinically benign lesions, P = 0.0368) and 17p (50% versus 21%).
Fluorescence in situ hybridization confirmed the comparative genomic
hybridization data of chromosomes 1p, 3q, and 6q, and revealed aneuploidy
in some tumors. Our results suggest that the development of
pheochromocytomas is associated with specific genomic aberrations, such as
losses of 1p, 3q, and 6q and gains of 9q and 17q. In particular, tumor
suppressor genes on chromosomes 1p and 3q may be involved in early
tumorigenesis, and deletions of chromosomes 6q and 17p in progression to
malignancy
MR imaging of clear cell sarcoma (malignant melanoma of the soft parts): A multicenter correlative MRI-pathology study of 21 cases and literature review
Objective. To evaluate MR imaging and pathology findings in order to define the characteristic features of clear cell sarcoma of the soft tissues (malignant melanoma of the soft parts). Design and patients. MR examinations of 21 patients with histologically proven clear cell sarcoma of the musculoskeletal system were retrospectively reviewed and assessed for shape, homogeneity, delineation, signal intensities on T1- and T2-weighted images, contrast enhancement, relationship with adjacent fascia or tendon, secondary bone involvement, and intratumoral necrosis. In 19 cases the pathology findings were available for review and for a comparative MR-pathology study. Results. On T1-weighted images, lesions were isointense (n=3), hypointense (n=7) or slightly hyperintense to muscle (n=11). Immunohistochemical examination was performed in 17 patients. All 17 specimens showed positivity for HMB-45 antibody. In nine of 11 lesions with slightly increased signal intensity on T1-weighted images, a correlative MR imaging-pathology study was possible. All nine were positive to HMB-45 antibody. Conclusions. Clear cell sarcoma of the musculoskeletal system often has a benign-looking appearance on MR images. In up to 52% of patients, this lesion with melanocytic differentiation has slightly increased signal intensity on T1-weighted images compared with muscle. As the presence of this relative higher signal intensity on T1-weighted images is rather specific for tumors displaying melanocytic differentiation, radiologists should familiarize themselves with this rare entity and include it in their differential diagnosis when confronted with a well- defined, homogeneous, strongly enhancing mass with slightly higher signal intensity compared with muscle on native T1-weighted images
BRAF(E600)-associated senescence-like cell cycle arrest of human naevi
Most normal mammalian cells have a finite lifespan(1), thought to constitute a protective mechanism against unlimited proliferation(2-4). This phenomenon, called senescence, is driven by telomere attrition, which triggers the induction of tumour suppressors including p16(INK4a) (ref. 5). In cultured cells, senescence can be elicited prematurely by oncogenes(6); however, whether such oncogene-induced senescence represents a physiological process has long been debated. Human naevi ( moles) are benign tumours of melanocytes that frequently harbour oncogenic mutations ( predominantly V600E, where valine is substituted for glutamic acid) in BRAF(7), a protein kinase and downstream effector of Ras. Nonetheless, naevi typically remain in a growth-arrested state for decades and only rarely progress into malignancy (melanoma)(8-10). This raises the question of whether naevi undergo BRAF(V600E)- induced senescence. Here we show that sustained BRAF(V600E) expression in human melanocytes induces cell cycle arrest, which is accompanied by the induction of both p16(INK4a) and senescence- associated acidic beta-galactosidase (SA-beta-Gal) activity, a commonly used senescence marker. Validating these results in vivo, congenital naevi are invariably positive for SA-beta-Gal, demonstrating the presence of this classical senescence-associated marker in a largely growth-arrested, neoplastic human lesion. In growth-arrested melanocytes, both in vitro and in situ, we observed a marked mosaic induction of p16(INK4a), suggesting that factors other than p16(INK4a) contribute to protection against BRAF(V600E)- driven proliferation. Naevi do not appear to suffer from telomere attrition, arguing in favour of an active oncogene-driven senescence process, rather than a loss of replicative potential. Thus, both in vitro and in vivo, BRAF(V600E)-expressing melanocytes display classical hallmarks of senescence, suggesting that oncogene-induced senescence represents a genuine protective physiological process.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62941/1/nature03890.pd
Integration of Gene Dosage and Gene Expression in Non-Small Cell Lung Cancer, Identification of HSP90 as Potential Target
BACKGROUND: Lung cancer causes approximately 1.2 million deaths per year worldwide, and non-small cell lung cancer (NSCLC) represents 85% of all lung cancers. Understanding the molecular events in non-small cell lung cancer (NSCLC) is essential to improve early diagnosis and treatment for this disease. METHODOLOGY AND PRINCIPAL FINDINGS: In an attempt to identify novel NSCLC related genes, we performed a genome-wide screening of chromosomal copy number changes affecting gene expression using microarray based comparative genomic hybridization and gene expression arrays on 32 radically resected tumor samples from stage I and II NSCLC patients. An integrative analysis tool was applied to determine whether chromosomal copy number affects gene expression. We identified a deletion on 14q32.2-33 as a common alteration in NSCLC (44%), which significantly influenced gene expression for HSP90, residing on 14q32. This deletion was correlated with better overall survival (P = 0.008), survival was also longer in patients whose tumors had low expression levels of HSP90. We extended the analysis to three independent validation sets of NSCLC patients, and confirmed low HSP90 expression to be related with longer overall survival (P = 0.003, P = 0.07 and P = 0.04). Furthermore, in vitro treatment with an HSP90 inhibitor had potent antiproliferative activity in NSCLC cell lines. CONCLUSIONS: We suggest that targeting HSP90 will have clinical impact for NSCLC patients
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