-
Mia Kim,
Tanja Grimmig,
Martin Grimm,
Maria Lazariotou,
Eva Meier,
Andreas Rosenwald, Igor Tsaur,
Roman Blaheta,
Uwe Heemann,
Christoph-Thomas Germer,
Ana Maria Waaga-Gasser,
Martin Gasser
[show abstract]
[hide abstract]
ABSTRACT: Regulatory T cells (Treg) expressing the transcription factor forkhead-box protein P3 (Foxp3) have been identified to counteract anti-tumor immune responses during tumor progression. Besides, Foxp3 presentation by cancer cells itself may also allow them to evade from effector T-cell responses, resulting in a survival benefit of the tumor. For colorectal cancer (CRC) the clinical relevance of Foxp3 has not been evaluated in detail. Therefore the aim of this study was to study its impact in colorectal cancer (CRC).
Gene and protein analysis of tumor tissues from patients with CRC was performed to quantify the expression of Foxp3 in tumor infiltrating Treg and colon cancer cells. The results were correlated with clinicopathological parameters and patients overall survival. Serial morphological analysis demonstrated Foxp3 to be expressed in cancer cells. High Foxp3 expression of the cancer cells was associated with poor prognosis compared to patients with low Foxp3 expression. In contrast, low and high Foxp3 level in tumor infiltrating Treg cells demonstrated no significant differences in overall patient survival.
Our findings strongly suggest that Foxp3 expression mediated by cancer cells rather than by Treg cells contribute to disease progression.
PLoS ONE 01/2013; 8(1):e53630. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Targeted drugs have significantly improved the therapeutic options for advanced renal cell carcinoma (RCC). However, resistance often develops, negating the benefit of these agents. In the present study, the molecular mechanisms of acquired resistance towards the histone deacetylase (HDAC) inhibitor valproic acid (VPA) in a RCC in vivo model were investigated. NMRI:nu/nu mice were transplanted with Caki-1 RCC cells and then treated with VPA (200 mg/kg/day). Controls remained untreated. Based on tumor growth dynamics, the mice were divided into "responders" and "non-responders" to VPA. Histone H3 and H4 acetylation and expression of cell signaling and cell cycle regulating proteins in the RCC mouse tumors were evaluated by Western blotting. Tumor growth of VPA responders was significantly diminished, whereas that of VPA non-responders even exceeded control values. Cdk1, 2 and 4 proteins were strongly enhanced in the non-responders. Importantly, Akt expression and activity were massively up-regulated in the tumors of the VPA non-responders. Chronic application (12 weeks) of VPA to Caki-1 cells in vitro evoked a distinct elevation of Akt activity and cancer cells no longer responded with cell growth reduction, compared to the short 2 week treatment. We assume that chronic use of an HDAC-inhibitor is associated with (re)-activation of Akt, which may be involved in resistance development. Consequently, combined blockade of both HDAC and Akt may delay or prevent drug resistance in RCC.
PLoS ONE 01/2013; 8(1):e53100. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Pharmacologic options for patients with castration-resistant prostate cancer are limited. It has been suggested that targeting intracellular molecules, which have been altered during neoplastic development, may slow tumor growth. Therefore, the growth-blocking potential of the histone deacetylase-inhibitor LBH589 and the multiple tyrosine kinase-inhibitor TKI258, applied alone or in combination, was investigated in a panel of prostate cancer cell lines. PC-3, DU-145 or LNCaP cells were treated with various concentrations of LBH589 and/or TKI258. Tumor cell growth, cell cycle regulating proteins, HDAC3- and HDAC4-expression and histone H3 and H4 acetylation were then evaluated by MTT assay and Western blotting. LBH589 dose-dependently blocked prostate cancer cell growth. In contrast, TKI258 did not down-regulate tumor cell growth up to a 1,000 nM dosage. LBH589 elevated histone H3 and H4 acetylation. The cell cycle regulators cyclin B, cyclin D1, cdk1 and cdk4 were down-regulated in PC-3, whereas the suppressor proteins p21 and p27 were up-regulated in LNCaP by LBH589. TKI258 up-regulated p27 in PC-3 or p21 in LNCaP and additionally elevated cyclin B, cyclin D1, cdk1 and cdk4 in both cell lines. Presumably, the increase in cyclin and cdk caused by TKI258 counteracts the benefit of p21 or p27 up-regulation, resulting in TKI258 non-responsiveness. The LBH589/TKI258-combination was not superior to the LBH589 single-drug use in terms of growth reduction. Obviously, TKI258 did not enhance the sensitivity of prostate cancer cells towards an HDAC based regimen. Therefore, the LBH589/TKI258-combination probably does not provide an optimum strategy in fighting advanced prostate cancer.
Investigational New Drugs 07/2012; · 3.36 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Chronic mTOR inhibition may induce resistance development in renal cell carcinoma (RCC). We analyzed whether long-term exposure of RCC cells to the mTOR-inhibitor RAD001 evokes resistance and whether additional targeting histone deacetylases (HDAC) by valproic acid (VPA) overcomes RAD001 resistance. It is demonstrated that responsiveness to either drug alone is lost over time, evidenced by increased cell growth, proliferation and de-differentiation. However, drug sensitivity was conserved when RAD001 and VPA were applied in concert. Molecular analysis particularly revealed strong re-activation of Akt under chronic RAD001 or diminished histone H3 acetylation under chronic VPA single drug exposure. Combined drug application did not inactivate Akt but rather resulted in H3 acetylation remaining high while RCC cell growth was still reduced. siRNA experiments revealed that histone H3 acetylation is responsible for preserving drug sensitivity in RCCs.
Cancer letters 05/2012; 324(1):83-90. · 4.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We evaluated whether low-dosed interferon alpha (IFNa) may augment the anti-tumor potential of the histone deacetylase (HDAC)-inhibitor valproic acid (VPA) on prostate cancer cells in vitro and in vivo. PC-3, DU-145, or LNCaP prostate cancer cells were treated with VPA (1 mM), IFNa (200 U/ml), or with the VPA-IFNa combination. Tumor cell growth, cell cycle progression, and cell cycle regulating proteins were then investigated by the MTT assay, flow cytometry, and western blotting. Tumor cell adhesion to endothelium or to immobilized extracellular matrix proteins, as well as migratory properties of the cells, were evaluated. Integrin α and β adhesion molecules and alterations of cell signaling pathways were analyzed. Finally, effects of the drug treatment on prostate cancer growth in vivo were determined in the NOD/SCID mouse model. VPA reduced tumor cell adhesion, migration, and growth in vitro. A much stronger anti-cancer potential was evoked by the VPA-IFNa combination, although IFNa in itself did not block growth or adhesion. The same effect was seen when tumor growth was evaluated in vivo. Molecular analysis revealed distinct elevation of histone H3 acetylation caused by VPA which was further up-regulated by VPA-IFNa, whereas IFNa alone did not alter H3 acetylation. The combinatorial benefit became obvious in Akt phosphorylation, p21 and p27 and integrin α1, α3, and β1 expression. Application of low-dosed IFNa to a VPA based regimen profoundly boosts the anti-tumor properties of VPA. The combined use of VPA and low-dosed IFNa may therefore be an innovative option in treating advanced prostate cancer. Prostate 72:1719-1735, 2012. © 2012 Wiley Periodicals, Inc.
The Prostate 04/2012; 72(16):1719-35. · 3.48 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The growth potential of PC3 prostate cancer cells, sensible (PC3(par)) or resistant (PC3(res)) to the mTOR inhibitor everolimus (RAD001) was investigated. Cell growth and proliferation of PC3(res) was similar to that of PC3(par), and late apoptosis increased in PC3(par) but decreased in PC3(res) following treatment with low dosed everolimus. PC3(res) accumulated in the G2/M-phase, accompanied by cdk1, cdk2 and cyclin B elevation. Knocking down cdk1 or cyclin B distinctly blocked the growth activity of PC3(res). One reason for everolimus resistance may be up-regulation of the cdk1-cyclin B complex in prostate cancer cells, leading to enhanced progression towards G2/M.
Cancer letters 09/2011; 313(1):84-90. · 4.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Single drug use has not achieved satisfactory results in the treatment of prostate cancer, despite application of increasingly widespread targeted therapeutics. In the present study, the combined impact of the mammalian target of rapamycin (mTOR)-inhibitor RAD001, the dual EGFr and VGEFr tyrosine kinase inhibitor AEE788 and the histone deacetylase (HDAC)-inhibitor valproic acid (VPA) on prostate cancer growth and adhesion in vitro was investigated.
PC-3, DU-145 and LNCaP cells were treated with RAD001, AEE788 or VPA or with a RAD-AEE-VPA combination. Tumor cell growth, cell cycle progression and cell cycle regulating proteins were then investigated by MTT-assay, flow cytometry and western blotting, respectively. Furthermore, tumor cell adhesion to vascular endothelium or to immobilized extracellular matrix proteins as well as migratory properties of the cells was evaluated, and integrin α and β subtypes were analyzed. Finally, effects of drug treatment on cell signaling pathways were determined.
All drugs, separately applied, reduced tumor cell adhesion, migration and growth. A much stronger anti-cancer effect was evoked by the triple drug combination. Particularly, cdk1, 2 and 4 and cyclin B were reduced, whereas p27 was elevated. In addition, simultaneous application of RAD001, AEE788 and VPA altered the membranous, cytoplasmic and gene expression pattern of various integrin α and β subtypes, reduced integrin-linked kinase (ILK) and deactivated focal adhesion kinase (FAK). Signaling analysis revealed that EGFr and the downstream target Akt, as well as p70S6k was distinctly modified in the presence of the drug combination.
Simultaneous targeting of several key proteins in prostate cancer cells provides an advantage over targeting a single pathway. Since strong anti-tumor properties became evident with respect to cell growth and adhesion dynamics, the triple drug combination might provide progress in the treatment of advanced prostate cancer.
BMC Cancer 08/2011; 11:375. · 3.01 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Our aim was to analyze the impact of the histone deacetylase (HDAC)-inhibitor valproic acid (VPA) on bladder cancer cell growth in vitro. RT-4, TCCSUP, UMUC-3, and RT-112 bladder cancer cells were treated with VPA (0.125-1 mmol/l) without and with preincubation periods of 3 and 5 days. Controls remained untreated. Tumor cell growth, cell cycle progression, and cell cycle-regulating proteins were investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry, and western blotting, respectively. Effects of VPA on histone H3 and H4 acetylation and HDAC3 and HDAC4 were also determined. Without preincubation, no tumor cell growth reduction was observed with 0.125 and 0.25 mmol/l VPA in TCCSUP, UMUC-3, and RT-112 cells, whereas 0.5 and 1 mmol/l VPA diminished the cell number significantly. VPA (0.25 mmol/l) did exert tumor growth-blocking effects after a 3-day preincubation. To achieve antitumor effects with VPA (0.125 mmol/l), a 5-day preincubation was necessary. A 3-day or 5-day preincubation was also necessary to distinctly delay cell cycle progression, with maximum effects at VPA (1 mmol/l). After the 5-day preincubation, the cell cycle-regulating proteins cdk1, cdk2, cdk4, and cyclins B, D1, and E were reduced, whereas p27 was enhanced. Diminished HDAC3 and 4 expression induced by VPA was accompanied by elevated acetylation of H3 and H4. VPA exerted growth-blocking properties on a panel of bladder cancer cell lines, commensurate with dose and exposure time. Long-term application induced much stronger effects than did shorter application and should be considered when designing therapeutic strategies for treating bladder carcinoma.
Anti-cancer drugs 08/2011; 22(10):1002-9. · 2.23 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The concept of molecular tumor targeting might provide new hope in the treatment of advanced prostate cancer. We evaluated metastasis blocking properties of the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and the mammalian target of rapamycin (mTOR) inhibitor RAD001 on prostate cancer cell lines. RAD001 or VPA were applied to PC-3 or LNCaP cells, either separately or in combination. Adhesion to vascular endothelium or to immobilized collagen, fibronectin or laminin was quantified. Migration and invasion were explored by a modified Boyden chamber assay. Integrin α and β subtypes were analyzed by flow cytometry, western blotting and RT-PCR. Effects of drug treatment on integrin related signaling, Akt and p70S6kinase activation, histone H3 and H4 acetylation were also determined. Separate application of RAD001 or VPA distinctly reduced tumor cell adhesion, migration and invasion, accompanied by elevated Akt activation and p70S6kinase de-activation. Integrin subtype expression was altered significantly by both compounds (VPA > RAD001). When both drugs were used in concert additive effects were observed on the migratory and invasive behavior but not on tumor-endothelium and tumor-matrix interaction. Separate mTOR or HDAC inhibition slows processes related to tumor metastasis. The RAD001-VPA combination showed advantage over VPA monotreatment with particular respect to migration and invasion. Ongoing studies are required to assess the relevance of VPA monotherapy versus VPA-RAD001 combination on tumor cell motility.
Clinical and Experimental Metastasis 03/2011; 28(5):479-91. · 3.52 Impact Factor
-
Igor Tsaur,
Athanasios Karalis,
Roman Blaheta,
Eva Juengel,
Stefan Vallo,
Ernst-Heinrich Scheuermann,
Heinz-Georg Kachel,
Ana-Maria Waaga-Gasser,
Anil Chandraker,
Nicholas Obermüller,
Michael Probst
[show abstract]
[hide abstract]
ABSTRACT: The aim of the current study was to explore the clinico-oncological characteristics, and the therapeutic and survival parameters, of renal transplant recipients who developed de novo transitional cell carcinoma (TCC) over a 30-year period at the authors' center.
Retrospective analysis of records from all registered patients who underwent kidney transplantation at the center between November 1979 and January 2010 who developed de novo TCC of the urinary tract.
From all 2001 patients analyzed during the study period, 21 recipients developed 19 TCCs of the bladder and 6 TCCs of the upper urinary tract. Among bladder TCCs, 13 (68.4%) cases were confined to mucosa (pTa or carcinoma in situ, n = 7) or submucosa (pT1, n = 6) and 6 others (31.6%) infiltrated the detrusor muscle (≥p T2); the grading distribution was 5 cases of G1, 6 of G2 and 8 of G3. All recurrent cases (n = 8) revealed local or systemic progression. The overall and tumor-specific patient survival rates were 80.2%, 54.0% and 30.0% and 84.9%, 67.4% and 58.9% for 1, 5 and 10 years, respectively.
In the light of the observed increased aggressiveness of TCC in renal transplant recipients, more frequent examinations and possibly more invasive follow-up protocols should be considered for patients with 1 or more risk factors for development of TCC. Urine cytology (including ureteral wash cytology) may be used as a reliable diagnostic tool in these patients. Prophylactic contralateral nephroureterectomy might be an option in patients at high risk.
The American Journal of the Medical Sciences 03/2011; 341(6):478-83. · 1.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The impact of the mTOR inhibitor RAD001 combined with the EGFr/VEGFr tyrosine kinase inhibitor AEE788 on prostate tumor cell growth, adhesion and migration was analyzed in vitro. The RAD001-AEE788 combination profoundly reduced tumor-endothelium and tumor-matrix contacts, suppressing cell growth and cell cycle progression. The underlying molecular mode of action depended on the cell phenotype, since cell cycle proteins, integrin subtype expression and integrin dependent signaling were altered in a different manner in PC-3 and DU-145 versus LNCaP prostate cancer cells. Simultaneous targeting of mTOR and VEGFr/EGFr related pathways may offer a novel therapeutic strategy for prostate cancer treatment.
Cancer letters 02/2011; 301(1):17-28. · 4.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To analyze the combined impact of the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and the mammalian target of rapamycin (mTOR) inhibitor RAD001 on prostate cancer cell growth.
PC-3, DU-145 and LNCaP cells were treated with RAD001, VPA or with an RAD001-VPA combination for 3 or 5 days. Tumor cell growth, cell cycle progression and cell cycle regulating proteins were then investigated by MTT assay, flow cytometry and Western blotting, respectively. Effects of drug treatment on cell signaling pathways were determined.
Separate application of RAD001 or VPA distinctly reduced tumor cell growth and impaired cell cycle progression. Significant additive effects were evoked when both drugs were used in concert. Particularly, the cell cycle regulating proteins cdk1, cdk2, cdk4 and cyclin B were reduced, whereas p21 and p27 were enhanced by the RAD001-VPA combination. Signaling analysis revealed deactivation of EGFr, ERK1/2 and p70S6k. Phosphorylation of Akt was diminished in DU-145 but elevated in PC-3 and LNCaP cells.
The RAD001-VPA combination exerted profound antitumor properties on a panel of prostate cancer cell lines. Therefore, simultaneous blockage of HDAC and mTOR related pathways should be considered when designing novel therapeutic strategies for treating prostate carcinoma.
Life sciences 02/2011; 88(9-10):418-24. · 2.56 Impact Factor
-
Igor Tsaur,
Anika Noack,
Ana Maria Waaga-Gasser,
Jasmina Makarevic,
Lars Schmitt,
Martin Kurosch,
Tanja Huesch,
Christoph Wiesner,
Steffen Wedel,
Georg Bartsch,
Hanns Ackermann,
Elsie Oppermann,
Maria Lazariotou,
Martin Gasser,
Axel Haferkamp,
Roman A Blaheta
[show abstract]
[hide abstract]
ABSTRACT: Chemokines play a critical role in tumor initiation, progression, and metastasis and have been associated with poor prognosis in diverse malignancies. The prognostic impact of chemokines for renal cell cancer (RCC) remains to be defined.
Patients diagnosed with RCC and operated between 07/07 and 05/11 were differentially assessed for expression profiles of a series of chemokines and their receptors by RT-qPCR and Western Blot analysis (tumor and adjacent normal tissue, n=37) and by Luminex for corresponding serum expression levels. Results were statistically correlated with clinicopathologic parameters.
Gene expression of CCL2, CCR7, CXCL12, CXCR3, CXCR5 and CX3CL1 chemokines was significantly down-regulated in tumor compared to normal tissue. The gene profile for CCR6 was positively correlated with tumor size and stage. A positive linear correlation was found between CXCL12 and tumor stage as well as between CX3CR1 and C-reactive protein. In contrast to clear cell RCCs those of a chromophobe type showed a significantly down-regulated gene expression for CCR6, CCL20, and CXCL12. The CXCR7 serum level was significantly increased in patients with tumor-related mortality during postoperative follow-up.
Chemokines may serve as novel diagnostic and prognostic biomarkers for RCC. Studies on larger collectives are required for further assessment of potential clinical application.
Cancer biomarkers: section A of Disease markers 01/2011; 10(5):195-204. · 1.08 Impact Factor
-
Igor Tsaur,
Martin Gasser,
Beatriz Aviles,
Jens Lutz,
Lydia Lutz,
Martin Grimm,
Volkmar Lange,
Kai Lopau,
Uwe Heemann,
Christoph-Thomas Germer,
Anil Chandraker,
Ana Maria Waaga-Gasser
[show abstract]
[hide abstract]
ABSTRACT: Chronic transplant dysfunction, a major impediment to long-term allograft survival, is caused by several factors including an ongoing alloimmune response termed chronic rejection. To define some of these factors further, we selected 107 patients mismatched to their donors from 623 patients transplanted at a single center. Patients were categorized according to their immunosuppressive treatment and further divided into those with stable or chronic allograft dysfunction. Donor human lymphocyte antigen allopeptide-specific T-cell lines were then generated from stable patients and those with biopsy-proven chronic allograft nephropathy. Increased amounts of CD4+CD25+ regulatory T cells (Tregs) and Treg-associated gene expression profiles were found in cell lines derived from the patients with stable compared with those with chronic allograft dysfunction. Furthermore, a higher percentage of Tregs was found in patients with stable graft function on tacrolimus-based compared with cyclosporine-based immunosuppression protocols. Patients with stable graft function had a significantly higher expression of interleukin (IL)-4 and IL-10, whereas the cytokines IL-2, IL-17, and interferon-γ were significantly higher in patients with allograft dysfunction in vitro. Thus, enhancing the operational role of naturally occurring donor-specific Tregs in allograft recipients by adjusting the immunosuppression protocol may be advantageous particularly for patients with ongoing chronic rejection.
Kidney International 01/2011; 79(9):1005-12. · 6.61 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Fatal post-transplant malignancies with a high proportion of genitourinary neoplasms represent a serious long-term challenge. With continuous improvement of the allograft and patient survival, cancer development after renal transplantation may soon turn to the leading morbidity cause. In a retrospective single-center study of 1990 renal transplant recipients between November 1979 and November 2009, records of patients with urological neoplasms including epidemiological, clinical and survival parameters were accessed. Sixty-six de novo urological malignancies in 58 recipients were recorded in the study period, being most common after skin cancers (15.6% of enregistered tumors). From these, 29 were renal cell cancers, including five neoplasms of transplanted kidney, 24 transitional cell carcinomas, 11 prostate carcinomas, and two germ cell carcinomas with incidence rates of 1.5%, 1.2%, 0.9% and 0.2%, respectively. The patient follow up was virtually complete. Tumor-related death was found in 44% of cases. By multivariate analysis, no influence of either duration of dialysis, mode or duration of immunosuppression, gender or age at transplantation on overall patient survival could be demonstrated. This study, documenting a 30-year single center experience, emphasizes the increased risk for urological neoplasms occuring after renal transplantation. Screening strategies for urological cancers should be optimized.
Cancer Science 11/2010; 101(11):2430-5. · 3.33 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: • To access the epidemiological, clinical and survival features of renal transplant patients with de novo renal cell carcinoma of native and graft kidneys.
• We performed a retrospective examination of the data of 2001 consecutive renal transplant recipients at our centre between November 1979 and January 2010.
• In the patient cohort examined, 30 renal cell carcinomas were observed in 26 individuals (incidence 1.5%) with 25 tumours in the native and five in allograft kidneys. Mean tumour size in surgical specimens was 44 ± 36 mm. The rate of papillary cancer was 37.5%. • After a mean follow-up of 58.6 ± 62.3 months, 15.4% of the patients died from cancer and 57.7% were in complete remission. • Overall and tumour-specific survival rates at 1, 5 and 10 years were 86.1%, 75.1% and 43.8%, and 90.4%, 83.5% and 66.8%, respectively.
• Due to increasingly improved survival after renal transplantation, de novo malignancies might soon become the main cause of intermediate- or long-term mortality. • Current data support an increased risk of renal cell carcinoma in renal transplant recipients in a particularly aggressive way, but low tendency for metachronous contralateral evolution. • With continuous radiological follow-ups, acceptable oncological outcome can be achieved. Graft tumours may have a favourable prognosis.
BJU International 11/2010; 108(2):229-34. · 2.84 Impact Factor
-
Martin Grimm,
Mia Kim,
Andreas Rosenwald,
Burkhard H A von Raden,
Burkhard von Rahden, Igor Tsaur,
Eva Meier,
Uwe Heemann,
Christoph-Thomas Germer,
Martin Gasser,
Ana Maria Waaga-Gasser
[show abstract]
[hide abstract]
ABSTRACT: Expression of apoptosis-related proteins on tumour cells has been shown in several experimental models to be an efficient mechanism for a counterattack against host anti-tumour immune responses in solid tumours. Here we provide a clinical evidence for such a tumour immune escape mechanism by demonstrating tumour to T cell-directed death receptor signalling (TRAIL/TRAIL-Receptor (TRAIL-R)) in colorectal cancer (CRC). In a series of patients with CRC and completed 5-year follow up, we investigated apoptosis and expression levels of apoptosis-related proteins. Gene and protein profiles in the tumours demonstrated intratumoural upregulated gene expression for Fas, Fas-L, TRAIL, TRAIL-R and TNF-alpha (RT-qPCR). Levels of terminaldeoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick-end labelling (TUNEL)-positive events were positively correlated with TRAIL-R1-expression on tumour infiltrating immune cells. Among the immune cells, preferentially CD8+ T cells were found to express TRAIL-R1 while serial immunostaining in the same patient tumours showed abundant apoptotic (TUNEL-positive) immune cells. In conclusion, our results in tumour samples from CRC patients suggest TRAIL-R1-mediated apoptotic depletion of infiltrating immune cells (CD8+) in response to TRAIL expression by the tumour itself. This supports the notion of an efficient escape from tumour immune response and thus evasion from the attack of activated CD8+ T cells. These findings may enhance our understanding of tumour progression in CRC and might be helpful for the development of TRAIL and its death receptor-based therapy.
European journal of cancer (Oxford, England: 1990) 08/2010; 46(12):2314-23. · 4.12 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In this study, we aimed to determine those clinical and pathologic features that are associated with pelvic lymph node metastasis in patients with transitional cell cancer of the bladder. Unlike previous studies, we particularly focused on intravesical tumor location.
We included 173 patients who underwent radical cystectomy and bilateral pelvic lymphadenectomy for muscle-invasive or high-risk superficial bladder cancer. Fifty patients (28.9%) presented with lymph node metastases. Tumor-related and personal characteristics were analyzed.
Lymph node positive disease occurred in association with an increasing pathologic tumor stage (P < 10(-6)) and with a decreasing differentiation status (P = 0.008). The rate of pelvic lymph node metastasis differed in primary tumors growing on different intravesical locations. Cancers located exclusively on the lateral bladder walls (P < 10(-5)) and tumors involving the lateral walls (P = 0.042) were highly correlated with lymph node positive disease. Posterior wall tumors were least associated with lymph node metastases compared with other tumor locations (P = 0.015). Focal tumor growths located on the lateral bladder wall and an increasing pathologic tumor stage and decreasing differentiation-status were identified as independent risk factors for the pelvic lymph node status.
For the first time we present the association of intravesical tumor location and the rate of lymph node metastasis in transitional cell cancer of the bladder. Our findings may ultimately contribute to a more individualized patient management.
The American Journal of the Medical Sciences 02/2010; 339(4):341-4. · 1.39 Impact Factor
