Epidermal growth factor (EGF) activates nuclear factor-kappaB through IkappaBalpha kinase-independent but EGF receptor-kinase dependent tyrosine 42 ph

Overexpression of epidermal growth factor (EGF) receptor and constitutive activation of nuclear factor-B (NF-B) are frequently encountered in tumor cells. Although EGF has been shown to induce NF-B activation, the mechanism is poorly understood. EGF activated NF-B DNA binding, induced NF-B reporter activity and the expression of antiapoptotic and cell-proliferative gene products. Interestingly, non-small cell lung adenocarcinoma cell lines (HCC827 and H3255), which exhibit EGFR amplification, showed ligand-independent activation of NF-B. Unlike tumor-necrosis factor (TNF), however, EGF failed to induce IB phosphorylation and ubiquitination and the activation of IB kinase (IKK). Although DN-IKK inhibited TNF-induced NF-B activity, DN-IKK had no effect on EGF-induced NF-B activation, suggesting that EGF-induced NF-B activation is IKK independent. Using dominant-negative plasmids, we also demonstrated the role of TRADD, TRAF2, NIK and Ras in EGF-induced NF-B activation. By using specific antibodies and IB plasmid, which is mutated at tyrosine 42 to phenylalanine, we show that EGF induced the tyrosine phosphorylation of IB at residue 42. Furthermore, EGF receptor kinase inhibitor blocked IB phosphorylation and consequent NF-B activation. Overall, our results indicate that tyrosine phosphorylation of IB at residue 42 is critical for EGF-induced NF-B activation pathway.

Activity of endovesical gemcitabine in BCG-refractory bladder cancer patients: a translational study

Intravesical gemcitabine (Gem) has shown promising activity against transitional cell carcinomas (TCC) of the bladder, with moderate urinary toxicity and low systemic absorption. The present phase II study evaluated the activity of biweekly intravesical treatment with Gem using a scheme directly derived from in vitro preclinical studies. Patients with Bacille Calmette-Guérin (BCG) -refractory Ta G3, T1 G1-3 TCC underwent transurethral bladder resection and then intravesical instillation with 2000 mg Gem diluted in 50 ml saline solution on days 1 and 3 for 6 consecutive weeks. Thirty-eight (95%) of the 40 patients showed persistent negative post-treatment cystoscopy and cytology 6 months after Gem treatment, while the remaining 2 patients relapsed at 5 and 6 months. At a median follow-up of 28 months, recurrences had occurred in 14 patients. Among these, four had downstaged (T) disease, three had a lower grade (G) lesion and three had a reduction in both T and G. Urinary and systemic toxicity was very low, with no alterations in biochemical profiles. In conclusion, biweekly instillation of Gem proved active in BCG-refractory Ta G3, T1 G1-3 TCC. Our results highlight the importance of preclinical studies using in vitro systems that adequately reproduce the conditions of intravesical clinical treatment to define the best therapeutic schedule.

Androgen withdrawal improves tumor hypoxia in prostate cancer

Around one-quarter of patients who receive radical treatment for prostate cancer subsequently develop progressive disease. The mechanisms underlying this malignant progression are, however, poorly elucidated. Recently, Milosevic and co-workers have investigated the effects of androgen withdrawal on prostate cancer hypoxia. Androgen withdrawal is known to result in tumor regression in the majority of patients, and is effective in combination with radiotherapy.

Genetic cooperation between p21Cip1 and INK4 inhibitors in cellular senescence and tumor suppression

Cell-cycle inhibitors of the Cip/Kip and INK4 families are involved in cellular senescence and tumor suppression. Some of these proteins, p21^Cip1, p16^INK4a and p15^INK4b, are coexpressed in response to antiproliferative signals such as cellular senescence resulting in cell-cycle arrest. To understand the roles of these inhibitors and their synergistic effect, we have characterized the growth properties and senescent behavior of primary cells deficient in p21^Cip1 and expressing an endogenous Cdk4^R24C (cyclin-dependent kinase) mutant (Cdk4^R24C knock-in cells) insensitive to INK4 proteins. Inactivation of both p21^Cip1 and INK4 pathways strongly cooperate in suppressing cellular senescence in vitro. These double mutant cells behavior as immortal cultures and display high sensitivity to cellular transformation by oncogenes. Moreover, mice double mutant in the INK4 and p21^Cip1 pathways (Cdk4^R24C; p21^Cip1-null mice) display an increased incidence of specific sarcomas, suggesting a significant cooperation between these two families of cell-cycle inhibitors in senescence responses and tumor suppression in vivo.

Postulate 5: the psychological burden of untreated cancer

The psychological burden of living with untreated cancer has less impact on the quality of life than unnecessary, but curative, therapy. The psychological effects of living for many years with untreated cancer are unknown; however, the evidence indicates it is the diagnosis of cancer that takes a psychological toll, whether patients are treated curatively or not. A companion study to the randomized trial of surgery versus watchful waiting in Sweden described above found no significant psychological difference at 5 years between the two study arms. The occurrence of worry, anxiety or depression was equal between the treatment and the observation arms. Surveillance is clearly stressful for some men; however, concern about PSA recurrence is common among both treated and untreated patients. Patients who are educated to appreciate the indolent natural history of most good-risk prostate cancers might avoid much of this anxiety. Further quality-of-life studies focusing on this issue are clearly warranted.