Showing papers by "Umar Mahmood published in 2006"

Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse.

Abstract: Activating KRAS mutations and p16Ink4a inactivation are near universal events in human pancreatic ductal adenocarcinoma (PDAC). In mouse models, KrasG12D initiates formation of premalignant pancreatic ductal lesions, and loss of either Ink4a/Arf (p16Ink4a/p19Arf) or p53 enables their malignant progression. As recent mouse modeling studies have suggested a less prominent role for p16Ink4a in constraining malignant progression, we sought to assess the pathological and genomic impact of inactivation of p16Ink4a, p19Arf, and/or p53 in the KrasG12D model. Rapidly progressive PDAC was observed in the setting of homozygous deletion of either p53 or p16Ink4a, the latter with intact germ-line p53 and p19Arf sequences. Additionally, KrasG12D in the context of heterozygosity either for p53 plus p16Ink4a or for p16Ink4a/p19Arf produced PDAC with longer latency and greater propensity for distant metastases relative to mice with homozygous deletion of p53 or p16Ink4a/p19Arf. Tumors from the double-heterozygous cohorts showed frequent p16Ink4a inactivation and loss of either p53 or p19Arf. Different genotypes were associated with specific histopathologic characteristics, most notably a trend toward less differentiated features in the homozygous p16Ink4a/p19Arf mutant model. High-resolution genomic analysis revealed that the tumor suppressor genotype influenced the specific genomic patterns of these tumors and showed overlap in regional chromosomal alterations between murine and human PDAC. Collectively, our results establish that disruptions of p16Ink4a and the p19ARF-p53 circuit play critical and cooperative roles in PDAC progression, with specific tumor suppressor genotypes provocatively influencing the tumor biological phenotypes and genomic profiles of the resultant tumors.

Identification of the target self-antigens in reperfusion injury

Abstract: Reperfusion injury (RI), a potential life-threatening disorder, represents an acute inflammatory response after periods of ischemia resulting from myocardial infarction, stroke, surgery, or trauma. The recent identification of a monoclonal natural IgM that initiates RI led to the identification of nonmuscle myosin heavy chain type II A and C as the self-targets in two different tissues. These results identify a novel pathway in which the innate response to a highly conserved self-antigen expressed as a result of hypoxic stress results in tissue destruction.

Particularities of the vasculature can promote the organ specificity of autoimmune attack.

Abstract: How certain autoimmune diseases target specific organs remains obscure. In the 'K/BxN' arthritis model, autoantibodies to a ubiquitous antigen elicit joint-restricted pathology. Here we have used intravital imaging to demonstrate that transfer of arthritogenic antibodies caused macromolecular vasopermeability localized to sites destined to develop arthritis, augmenting its severity. Vasopermeability depended on mast cells, neutrophils and FcgammaRIII but not complement, tumor necrosis factor or interleukin 1. Unexpectedly, radioresistant FcRgamma-expressing cells in an organ distant from the joint were required. Histamine and serotonin were critical, and systemic administration of these vasoactive amines recapitulated the joint localization of immune complex-triggered vasopermeability. We propose that regionally distinct vascular properties 'interface' with immune effector pathways to foster organ-specific autoimmune damage, perhaps explaining why arthritis accompanies many human infectious and autoimmune disorders.

Near infrared thoracoscopy of tumoral protease activity for improved detection of peripheral lung cancer.

Abstract: Improvement in tumor detection using "smart" probes in combination with microcatheter fluorescence thoracoscopy was evaluated in a mouse model. These imaging probes increase in fluorescence intensity after protease activation; cathepsin B is a major activator of the probes used in this study. Lewis lung carcinoma cells were orthotopically implanted in the subpleural lung parenchyma. Two activatable near infrared (NIR) probes with different excitation and emission wavelength were administered intravenously to determine whether wavelength would modulate target to background ratio (TBR). Mice were selectively intubated and thoracoscopy performed. A 0.8 mm outer diameter imaging catheter was used to record simultaneous white-light (anatomic) and NIR (protease expression) images. At both wavelength pairs evaluated (680/700 and 750/780 nm excitation/emission), the intrinsic luminosity differences between tumors and normal lung in uninjected animals was low (p > 0.3 and p = 0.4, respectively and TBR near 1). In mice receiving protease probes IV, tumors were significantly more fluorescent than adjacent lung (p < 0.0005 for 680/700 and p < 0.006 for 750/780) and TBR increased to approximately 9-fold. Confirmatory fluorescence microscopy and immunohistochemistry were similar and revealed that normal lung had very low levels when compared to tumors of cathepsin B and probe fluorescence. In conclusion, protease sensitive imaging probes selective for cathepsin B, imaged with NIR microcatheters, significantly increase the TBR, making small peripheral lung tumors more readily apparent. Such an approach may be a useful adjunct in staging or restaging patients with lung cancer to find minimal disease in the pleural and subpleural space.

N-Cadherin and Keratinocyte Growth Factor Receptor Mediate the Functional Interplay between Ki-RASG12V and p53V143A in Promoting Pancreatic Cell Migration, Invasion, and Tissue Architecture Disruption

Abstract: The genetic basis of pancreatic ductal adenocarcinoma, which constitutes the most common type of pancreatic malignancy, involves the sequential activation of oncogenes and inactivation of tumor suppressor genes. Among the pivotal genetic alterations are Ki-RAS oncogene activation and p53 tumor suppressor gene inactivation. We explain that the combination of these genetic events facilitates pancreatic carcinogenesis as revealed in novel three-dimensional cell (spheroid cyst) culture and in vivo subcutaneous and orthotopic xenotransplantation models. N-cadherin, a member of the classic cadherins important in the regulation of cell-cell adhesion, is induced in the presence of Ki-RAS mutation but subsequently downregulated with the acquisition of p53 mutation as revealed by gene microarrays and corroborated by reverse transcription-PCR and Western blotting. N-cadherin modulates the capacity of pancreatic ductal cells to migrate and invade, in part via complex formation with keratinocyte growth factor receptor and neural cell adhesion molecule and in part via interaction with p120-catenin. However, modulation of these complexes by Ki-RAS and p53 leads to enhanced cell migration and invasion. This preferentially induces the downstream effector AKT over mitogen-activated protein kinase to execute changes in cellular behavior. Thus, we are able to define molecules that in part are directly affected by Ki-RAS and p53 during pancreatic ductal carcinogenesis, and this provides a platform for potential new molecularly based therapeutic interventions.