Biomedical subjects

Jareer Kassis

Publications and source records attributed to Jareer Kassis.

8 recordsLinked to original sources

PubMed2005

Tumor microenvironment: what can effusions teach us?

Malignant effusions, which are composed of malignant pleural and peritoneal fluid, are an unusual manifestation of cancer and frequently portend a poor prognosis. Neoplastic cells that disseminate into cavities containing effusions are highly metastatic and possess a strong autonomous proliferative drive while concurrently being stimulatory of exudative effusions. Most effusions will respond to transient therapeutic intervention, including the obliteration of potential space via pleurodesis. Cure, however, is rare, thus making effusions a biologically, biochemically, and clinically important topic of study. The local microenvironment that supports malignant growth, invasion, and dissemination of the solid primary tumor into the vasculature is composed of activated stroma that includes scaffolding consisting of materials that promote the tumor function, and vascular structures to provide conduits for travel and nutrient delivery. Less is understood about the tumor-cell microenvironment in malignant effusions. The fluid nature of such a microenvironment when compared with the solid primary tumor may have significant implications for disease dissemination and progression. Dissecting the signaling activity and components of such microenvironments will improve our understanding and ultimately our ability to provide better patient care.

Ascitic Fluid↗

PubMed2004

DU145 human prostate carcinoma invasiveness is modulated by urokinase receptor (uPAR) downstream of epidermal growth factor receptor (EGFR) signaling.

Tumor cell motility and invasion have been linked to upregulated signaling from both the epidermal growth factor receptor (EGFR) and that for urokinase-type plasminogen activator (uPAR). However, we do not know whether these events are interdependent or unrelated, despite the obvious diagnostic and therapeutic implications. Gene microarray analyses have suggested that EGFR signaling via phospholipase C-gamma (PLCgamma) induces uPAR transcription. We utilized two sublines of the DU145 human prostate carcinoma cell line that are genetically engineered to differentially activate the EGFR/PLCgamma cascade and are variously invasive in vitro and in vivo. uPAR protein levels in these cells were found to be dependent on PLC signaling, pharmacologic inhibition of PLC signaling reduced uPAR expression. To determine whether uPAR was a required element in EGFR-mediated invasion, we stably expressed uPAR cDNA in either sense or antisense orientation in the two DU145 sublines. Interestingly, uPA production was modulated in parallel, although to a lesser degree, with uPAR in these sublines. Antisense to uPAR significantly restricted invasion of the highly invasive DU145 WT cells through Matrigel and reduced aggressiveness of tumors in nude mice. Up-regulation of uPAR significantly increased the invasiveness of the moderately invasive DU145 parental (DU145 P) cells through Matrigel, but this increased invasiveness was not seen in mice. uPA activity appears to contribute to invasiveness at least through Matrigel, as antibody to uPA or amiloride limited the transmigration. These results support a model of tumor invasion promoted by autocrine EGFR signaling involving reinforcing altered gene expression, of uPAR at least, that further induces cell motility. Herein, a number of key molecules whose expression levels are interrelated, including both EGFR and uPAR, are required but none are sufficient in the absence of other keys molecules in promoting tumor progression.

Amiloride↗

PubMed2003

Epidermal growth factor receptor-stimulated activation of phospholipase Cgamma-1 promotes invasion of head and neck squamous cell carcinoma.

Lymph node metastasis and local invasion of head and neck squamous cell carcinoma (HNSCC) is associated with a poor prognosis. However, little is known about the factors governing tumor cell invasion in HNSCC. Phospholipase Cgamma-1 (PLCgamma-1) contributes to tumor cell invasion in experimental systems when activated by the epidermal growth factor receptor (EGFR). We hypothesized that EGFR overexpression in HNSCC mediates invasion via PLCgamma-1. On EGFR ligand stimulation, phosphorylation of PLCgamma-1 increased in all of the HNSCC cell lines tested (4 of 4). In the presence of EGFR-specific tyrosine kinase inhibitor (PD153035) or an anti-EGFR antibody (C225), PLCgamma-1 activation was abrogated indicating that PLCgamma-1 was downstream of EGFR. Blocking cellular PLC with an inhibitor (U73122) reduced inositol phosphate turnover in all of the HNSCC cell lines examined, and treatment with the PLC inhibitor or antisense oligonucleotides targeting PLCgamma-1 significantly reduced in vitro invasiveness of HNSCC cell lines through Matrigel. To determine the clinical relevance of these findings, we compared levels of PLCgamma-1 in tumor and paired normal tissue from 33 patients with HNSCC. PLCgamma-1 levels were significantly higher (P < 0.0001) in the tumors compared with the normal mucosa of HNSCC patients. Levels of activated PLCgamma-1 were analyzed in 20 patients. Tumors expressed higher levels of phosphorylated PLCgamma-1 compared with normal adjacent mucosa (P = 0.05). Thus, PLCgamma-1 may mediate invasion and metastasis downstream of EGFR in HNSCC.

Aged↗

PubMed2003

Calcium as a molecular target in angiogenesis.

The plethora of cellular pathways and events involved in angiogenesis are a prime example of the widespread role of calcium ion flux in biological functions. Indeed, calcium is a main point of intersection for many distinct molecular signaling pathways that promote and modulate angiogenesis. Here, we illustrate some of the important aspects of calcium induction, function, downstream effects, and resulting cellular changes that ensue. We describe some of the main mechanisms of calcium regulation in cells as well as intracellular and cross-membrane flux, highlighting key players that are known to facilitate these events. We review some of the major signaling pathways that tie into angiogenesis, and also describe how cellular phenotypic changes that occur during angiogenesis require processes rich in calcium ion stimulation of gradient shifts. Lastly, we hypothesize on current thinking of the role of calcium as a whole in angiogenic cellular function and propose new insight into calcium as a universal effector molecule and a prime target for therapeutic intervention.

Calcium↗

PubMed2002

EBV-expressing AGS gastric carcinoma cell sublines present increased motility and invasiveness.

Tumor invasion marks a critical point in cancer progression; it is a harbinger of morbidity and mortality. Thus, the cellular events that enable the invasive phenotype are under intense investigation. Epstein-Barr virus (EBV) is associated with a number of cancers, including Burkitt lymphoma (BL) and nasopharyngeal carcinoma (NPC) and is suspected to contribute to their tumorigenesis. On average, 8% of gastric carcinomas have been shown to carry this virus. To explore whether the presence of EBV in gastric carcinoma contributes to tumor progression in this predominantly invasive carcinoma, we examined a panel of 2 in vitro EBV-infected human gastric cancer cell line sublines and their mock-infected AGS parental control line. We found EBV infection caused a marked increase in transmigration of a Matrigel barrier (415% and 303%, p < 0.05, for the 2 infected lines). This correlated with increased motility of these sublines (233% and 140%, p < 0.05). As this pattern of increased motility leading to a more pronounced enhancement of invasion has been noted in other tumor cells, we explored the roles of autocrine signaling pathways previously implicated in carcinoma motility and invasion. Inhibitors to the epidermal growth factor receptor (EGFR) (PD153035), phospholipase C (PLC) (U73122), extracellular-signal regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) (PD089035) and PI-3 kinase (Wortmannin) were not informative. These data suggest that EBV increases migration of AGS cells by a mechanism independent of these autocrine growth factor-induced pathways. Instead, we found that the EBV-infected cells presented increased focal adhesion kinase (FAK) phosphorylation. These findings suggest a role for integrin-mediated signaling in promoting EBV-associated invasiveness.

Carcinoma, Signet Ring Cell↗

PubMed2002

Motility is rate-limiting for invasion of bladder carcinoma cell lines.

Induced migration of tumor cells is generally considered to be one critical step in cancer progression to the invasive and metastatic stage. The implicit caveat of studies that show this is that other, unknown, signaling pathways and biophysical events are actually the operative rate-limiting steps, and not motility per se. Thus, to examine the hypothesis that motility is a single, but overall rate-limiting function required for invasion, disparate motility processes need be blocked with concordant effects on tumor invasion. Recently, we and others have described two signaling pathways that are critical to growth factor-induced motility but not mitogenesis. The key molecular switches are phospholipase C-gamma (PLCgamma) and calpain for cytoskeletal reorganization and rear detachment, respectively. We examined this hypothesis in a highly invasive tumor, bladder carcinoma. Three different human tumor cell lines, 253J-B-V, UMUC and T-24, were tested for invasiveness in vitro by transmigration of a Matrigel barrier. Inhibiting PLCgamma with the pharmacologic agent U73122 or the molecular dominant-negative PLCz construct reduced both invasiveness and motility. The same was noted when calpain was blocked using calpain inhibitor I (ALLN). These results demonstrate that one interventional target for limiting invasion is not necessarily an individual motility pathway but rather cell migration per se.

Calpain↗

PubMed2002

Growth factor-induced cell motility in tumor invasion.

Tumor progression to the invasive and metastatic states dramatically enhances the morbidity and mortality of cancer. Rational therapeutic interventions will only be possible when we understand the molecular mechanisms governing the cell behavior underlying this transformation. For invasion, a subpopulation of tumor cells must recognize the extracellular matrix barrier, modify the barrier, migrate through the barrier, and then proliferate in the adjacent but ectopic locale. Prevention of any one of these steps would prevent invasion, but determining the most sensitively dysregulated step should provide the most promising therapeutic index. In many invasive tumors, upregulation of active motility is stimulated by growth factor receptor signaling, the EGF receptor being the most frequently implicated. Two key downstream molecular switches, PLCgamma and m-calpain, are required for growth factor-induced motility but not basal, matrix-stimulated motility. Inhibition of either of these enzymes blocks in vitro and in vivo invasion of prostate, breast, and bladder carcinomas and glioblastomas. These represent novel and potentially selective targets for drug development. Future advances in the imaging of tumors in animals and ex vivo organ culture systems should provide additional new targets.

Animals↗

PubMed2002

Luteinizing hormone-releasing hormone agonist limits DU-145 prostate cancer growth by attenuating epidermal growth factor receptor signaling.

PURPOSE: Advanced prostate cancer is treated initially by central suppression of androgen production by luteinizing hormone-releasing hormone (LHRH) agonists. Intriguingly, even hormone-independent cancers often show some, if only slight, growth retardation when these agonists are delivered in pharmacological doses. Previous studies have shown in cell lines and animal xenograft models that activation of peripheral LHRH receptors on prostate carcinoma cells lead to growth suppression. In parallel, there is a decrease of epidermal growth factor receptors (EGFRs) and activity. Because autocrine EGFR stimulation exists in most, if not all, prostate carcinomas and is required for cell proliferation, we asked whether LHRH signaling cross-attenuated EGFR to limit tumor growth. One possible mechanism was suggested by LHRH receptors triggering phospholipase-C (PLC) to activate protein kinase C (PKC) because PKC activation limits EGFR tyrosine kinase activity by phosphorylating EGFR at threonine 654. EXPERIMENTAL DESIGN: To determine the role of this cross-attenuation mechanism, we mutated the threonine 654 amino acid to an alanine (A654) to abrogate this inhibition. DU-145 cells stably expressing wild-type and A654 EGFR were grown as xenografts in the s.c. space of athymic mice. RESULTS: DU-145 cells, overexpressing wild-type EGFR, formed tumors in athymic mice that were inhibitable by goserelin acetate (Zoladex). Tumors expressing the A654 EGFR were resistant to this growth inhibition. These results paralleled in vitro studies in which goserelin acetate blocked proliferation of the WT DU-145 but not A654 DU-145 cells. CONCLUSIONS: These data support the model of LHRH agonists preventing EGFR-mediated tumor growth through a PKC pathway. This suggests new targets of modulatory intervention to limit the growth of androgen-independent prostate carcinomas.

Animals↗