BMC Cancer - Latest Articles

The potential biomarkers in predicting pathologic response of breast cancer to three different chemotherapy regimens

Linbo Wang — 2009-07-11T00:00:00Z

Background: Preoperative chemotherapy (PCT) has become the standard of care in locally advanced breast cancer. The identification of patient-specific tumor characteristics that can improve the ability to predict response to therapy would help optimize treatment, improve treatment outcomes, and avoid unnecessary exposure to potential toxicities. This study is to determine whether selected biomarkers could predict pathologic response (PR) of breast tumors to three different PCT regimens, and to identify a subset of patients who would benefit from a given type of treatment. Methods: 118 patients with primary breast tumor were identified and three PCT regimens including DEC (docetaxel+epirubicin+cyclophosphamide), VFC (vinorelbine/vincristine+5-fluorouracil+cyclophosphamide) and EFC (epirubicin+5-fluorouracil+cyclophosphamide) were investigated. Expression of steroid receptors, HER2, P-gp, MRP, GST-pi and Topo-II was evaluated by immunohistochemical scoring on tumor tissues obtained before and after PCT. The PR of breast carcinoma was graded according to Sataloff's classification. Chi square test, logistic regression and Cochran-Mantel-Haenszel assay were performed to determine the association between biomarkers and PR, as well as the effectiveness of each regimen on induction of PR. Results: There was a clear-cut correlation between the expression of ER and decreased PR to PCT in all three different regimens (p<0.05). HER2 expression is significantly associated with increased PR in DEC regimen (p<0.05), but not predictive for PR in EFC and VFC groups. No significant correlation was found between biomarkers PgR, Topo-II, P-gp, MRP or GST-pi and PR to any tested PCT regimen. After adjusted by a stratification variable of ER or HER2, DEC regimen was more effective in inducing PR in comparison with VFC and EFC regimens. Conclusions: ER is an independent predictive factor for PR to PCT regimens including DEC, VFC and EFC in primary breast tumors, while HER2 is only predictive for DEC regimen. Expression of PgR, Topo-II, P-gp, MRP and GST-pi are not predictive for PR to any PCT regimens investigated. Results obtained in this clinical study may be helpful for the selection of appropriate treatments for breast cancer patients.

Molecular fingerprinting of radiation resistant tumors: Can we apprehend and rehabilitate the suspects?

Charles Rosser — 2009-07-09T00:00:00Z

Radiation therapy continues to be one of the more popular treatment options for localized prostate cancer. One major obstacle to radiation therapy is that there is a limit to the amount of radiation that can be safely delivered to the target organ. Emerging evidence suggests that therapeutic agents targeting specific molecules might be combined with radiation therapy for more effective treatment of tumors. Recent studies suggest that modulation of these molecules by a variety of mechanisms (e.g., gene therapy, antisense oligonucleotides, small interfering RNA) may enhance the efficacy of radiation therapy by modifying the activity of key cell proliferation and survival pathways such as those controlled by Bcl-2, p53, Akt/PTEN and cyclooxygenase-2. In this article, we summarize the findings of recent investigations of radiosensitizing agents in the treatment of prostate cancer.

Downregulation of SFRP5 expression and its inverse correlation with those of MMP-7 and MT1-MMP in gastric cancer

Chenghai Zhao — 2009-07-09T00:00:00Z

Background: As negative regulators in Wnt signaling, Secreted Frizzled-Related Proteins (SFRPs) are downregulated in a series of human cancers; and specifically, some matrix metalloproteinases (MMPs), including MMP-2, MMP-7, MMP-9 and MT1-MMP, are frequently overexpressed in gastric cancer. The aim of this study is to determine the expression status of SFRP5 in gastric cancer and explore the correlation between both the expression of SFRP5 and that of these MMPs in this cancer. Methods: Expression of SFRP5, MMP-2, MMP-7, MMP-9 and MT1-MMP was determined by real-time PCR, RT-PCR or Western blotting. The methylation status of SFRP5 was detected by Methylation-specific PCR (MSP). Cell lines with SFRP5 methylation were demethylated by a DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (DAC). KatoIII cells were transfected with pcDNA3.1 SFRP5 vector to strengthen SFRP5 expression. To abrogate SFRP5 expression in MKN1 cells, SFRP5 RNAi plamid was used to transfect them. Results: SFRP5 expression was remarkably downregulated in 24 of 32 primary gastric cancer specimens, and even was not detectable in 5 of 8 gastric cancer cell lines. MMP-7 and MT1-MMP mRNA showed a stronger expression in these 24 specimens compared to the other 8 specimens. They also showed higher levels in gastric cancer cell lines AGS and NCI-N87 which had no SFRP5 expression, compared to MKN1 with strong SFRP5 expression. However, they were significantly downregulated, with SFRP5 expression restored in AGS and NCI-N87; and were considerably upregulated with it abrogated in MKN1. Conclusions: The results indicate there are frequent occurrences of downregualtion of SFRP5 expression in gastric cancer, primarily due to SFRP5 methylation. It seems to be responsible for the upregulation of MMP-7 expression and MT1-MMP expression on the ground that they are inversely correlated with SFRP5 expression.

Integrin alpha6B beta4 inhibits colon cancer cell proliferation and c-Myc activity

Anders Dydensborg — 2009-07-09T00:00:00Z

Background: Integrins are known to be important contributors to cancer progression. We have previously shown that the integrin beta4 subunit is upregulated in primary colon cancer. Its partner, the integrin alpha6 subunit, exists as two different mRNA splice variants, alpha6A and alpha6B, that differ in their cytoplasmic domains but evidence for distinct biological functions of these alpha6 splice variants is still lacking. Methods: In this work, we first analyzed the expression of integrin alpha6A and alpha6B at the protein and transcript levels in normal human colonic cells as well as colorectal adenocarcinoma cells from both primary tumors and established cell lines. Then, using forced expression experiments, we investigated the effect of alpha6A and alpha6B on the regulation of cell proliferation in a colon cancer cell line. Results: Using variant-specific antibodies, we observed that alpha6A and alpha6B are differentially expressed both within the normal adult colonic epithelium and between normal and diseased colonic tissues. Proliferative cells located in the lower half of the glands were found to predominantly express alpha6A, while the differentiated and quiescent colonocytes in the upper half of the glands and surface epithelium expressed alpha6B. A relative decrease of alpha6B expression was also identified in primary colon tumors and adenocarcinoma cell lines suggesting that the alpha6A/alpha6B ratios may be linked to the proliferative status of colonic cells. Additional studies in colon cancer cells showed that experimentally restoring the alpha6A/alpha6B balance in favor of alpha6B caused a decrease in cellular S-phase entry and repressed the activity of c-Myc. Conclusions: The findings that the alpha6B beta4 integrin is expressed in quiescent normal colonic cells and is significantly down-regulated in colon cancer cells relative to its alpha6Abeta4 counterpart are consistent with the anti-proliferative influence and inhibitory effect on c-Myc activity identified for this alpha6B beta4 integrin. Taken together, these findings point out the importance of integrin variant expression in colon cancer cell biology.

Health - related quality of life of Kuwaiti women with breast cancer: a comparative study using the EORTC Quality of Life Questionnaire.

Shafika Alawadi — 2009-07-08T00:00:00Z

Background: The Kuwaiti perspective on quality of life (QOL) in breast cancer is important because it adds the contribution from a country where the disease affects women at a relatively younger age and seems to be more aggressive. We used the EORTC QLQ - C30 and its breast-specific module (BR-23) to highlight the health-related QOL of Kuwaiti women with breast cancer, in comparison with the international data, and assessed the socio-demographic and clinical variables that predict the five functional scales and global QOL (GQOL) scale of the QLQ -C30.MethodParticipants were consecutive clinic attendees for chemotherapy, in stable condition, at the Kuwait Cancer Control Center. Results: The 348 participants were aged 20 -81 years (mean 48.3, SD 10.3); 58.7% had stages III and IV disease. Although the mean scores for QLQ- C30 (GQOL, 45.3; and five functional scales, 52.6% -61.2%) indicated that the patients had poor to average functioning, only 5.8% to 11.2 % had scores that met the 66% criterion for more severe symptoms. Most (47.8% -70.1%) met the >66% criterion for "good functioning" on the BR-23 functional scales. The mean scores of the QLQ - C30 indicated that, despite institutional supports, Kuwaiti women had clinically significantly poorer global QOL and functional scale scores, and more intense symptom experience, in comparison with the international data (i.e., >/=10% difference between groups). For the BR-23, Kuwaiti women seemed to have clinically significantly better functional scale scores, but more severe symptoms, especially systemic side effects and breast symptoms. Younger women had poorer HRQOL scores. In regression analysis, social functioning accounted for the highest proportion of variance for GQOL. Conclusion: The relatively high number that met the criterion for good functioning on the functional scales is an evidence base to boost national health education about psychosocial prognosis in cancer. In view of the poor performance on the symptom scales, clinicians treating Kuwaiti women with breast cancer should prepare them for the acute toxicities of treatment and address fatigue. The findings call for the institution of a psycho-oncology service to address psycho-social issues.

CD133 antigen expression in ovarian cancer

Gabriella Ferrandina — 2009-07-07T00:00:00Z

Background: Much attention has been recently focused on the role of cancer stem cells (CSCs) in the initiation and progression of solid malignancies. Since CSCs are able to proliferate and self-renew extensively, thus sustaining tumor growth, the identification of CSCs through their antigenic profile might have relevant clinical implications. In this context, CD133 antigen has proved to be a marker of tumor cells with stemness features in several human malignancies.The aim of the study was to investigate the clinical role of the immunohistochemically assessed expression of CD133 in a large single Institution series of ovarian cancer patients. Methods: The study included 160 cases admitted to the Gynecologic Oncology Unit, Catholic University of Campobasso and Rome. CD133 antigen was identified by the monoclonal mouse anti-CD133-1 antibody (clone CD133 Miltenyi biotec). Results: In the overall series CD133 positive tumor cells were observed in 50/160 (31.2%) cases. A diffuse cytoplasmic pattern was identified in 30/50 (60.0%), while an apical cytoplasmic pattern was found in 20/50 (40.0%) of CD133 positive tumors.As of September 2008, the median follow up was 37 months (range: 2-112). During the follow up period, progression and death of disease were observed in 123 (76.9%), and 88 (55.0%) cases, respectively. There was no difference in TTP between cases with negative (median TTP= 23 months) versus positive CD133 expression (median TTP= 24 months) (p value=0.3). Similar results were obtained for OS. When considering the TTP and OS curves according to the pattern of CD133 expression, a trend to a worse prognosis for cases with diffuse cytoplasmic versus the apical cytoplasmic pattern was documented, although the statistical significance was not reached. Conclusions: The immunohistochemical assessment of CD133 expression seems not to provide additional prognostic information in ovarian cancer patients. The role of the different pattern of CD133 immunoreaction deserves further investigation in a larger series.

Neuropilin-2 expression in breast cancer: correlation with lymph node metastasis, poor prognosis, and regulation of CXCR4 expression

Hironao Yasuoka — 2009-07-07T00:00:00Z

Background: Neuropilin-2 (Nrp2) is a receptor for vascular endothelial growth factor-C (VEGF-C), which is a well-known lymphangiogenic factor and plays an important role in lymph node metastasis of various human cancers, including breast cancer. Recently, Nrp2 was shown to play a role in cancer by promoting tumor cell metastasis. CXC chemokine receptor 4 (CXCR4) also promotes tumor metastasis. In the previous studies, we demonstrated that VEGF-C and cytoplasmic CXCR4 expressions were correlated with poorer patient prognosis (BMC Cancer 2008,8:340; Breast Cancer Res Treat 2005, 91:125-132). Methods: The relationship between Nrp2 expression and lymph node metastasis, VEGF-C expression, CXCR4 expression, and other established clinicopathological variables (these data were cited in our previous papers), including prognosis, was analyzed in human breast cancer. Effects of neutralizing anti-Nrp2 antibody on CXCR4 expression and chemotaxis were assessed in MDA-MB-231 breast cancer cells. Results: Nrp2 expression was observed in 53.1 % (60 of 113) of the invasive breast carcinomas. Nrp2 expression was significantly correlated with lymph node metastasis, VEGF-C expression, and cytoplasmic CXCR4 expression. Survival curves determined by the Kaplan-Meier method showed that Nrp2 expression was associated with reduced overall survival. In multivariate analysis, Nrp2 expression emerged as a significant independent predictor for overall survival. Neutralizing anti-Nrp2 antibody blocks cytoplasmic CXCR4 expression and CXCR4-induced migration in MDA-MB-231 cells. Conclusions: Nrp2 expression was correlated with lymph node metastasis, VEGF-C expression, and cytoplasmic CXCR4 expression. Nrp2 expression may serve as a significant prognostic factor for long-term survival in breast cancer. Our data also showed a role for Nrp2 in regulating cytoplasmic CXCR4 expression in vitro.

DDEC: Dragon database of genes implicated in esophageal cancer

Magbubah Essack — 2009-07-06T00:00:00Z

Background: Esophageal cancer ranks eighth in order of cancer occurrence. Its lethality primarily stems from inability to detect the disease during the early organ-confined stage and the lack of effective therapies for advanced-stage disease. Moreover, the understanding of molecular processes involved in esophageal cancer is not complete, hampering the development of efficient diagnostics and therapy. Efforts made by the scientific community to improve the survival rate of esophageal cancer have resulted in a wealth of scattered information that is difficult to find and not easily amendable to data-mining. To reduce this gap and to complement available cancer related bioinformatic resources, we have developed a comprehensive database (Dragon Database of Genes Implicated in Esophageal Cancer) with esophageal cancer related information, as an integrated knowledge database aimed at representing a gateway to esophageal cancer related data.DescriptionManually curated 529 genes differentially expressed in EC are contained in the database. We extracted and analyzed the promoter regions of these genes and complemented gene-related information with transcription factors that potentially control them. We further, precompiled text-mined and data-mined re-ports about each of these genes to allow for easy exploration of information about associations of EC-implicated genes with other human genes and proteins, metabolites and enzymes, toxins, chemicals with pharmacological effects, disease concepts and human anatomy. The resulting database, DDEC, has a useful feature to display potential associations that are rarely reported and thus difficult to identify. Moreover, DDEC enables inspection of potentially new 'association hypotheses' generated based on the precompiled reports. Conclusions: We hope that this resource will serve as a useful complement to the existing public resources and as a good starting point for researchers and physicians interested in EC genetics. DDEC is freely accessible to academic and non-profit users at http://apps.sanbi.ac.za/ddec/. DDEC will be updated twice a year.

Response of the primary tumor in symptomatic and asymptomatic stage IV colorectal cancer to combined interventional endoscopy and palliative chemotherapy

Silke Cameron — 2009-07-01T00:00:00Z

[Background] The treatment of the primary tumor in advanced metastatic colorectal cancer (CRC) is still a matter of discussion. Little attention has thus far been paid to the endoscopically observable changes of the primary in non-curatively resectable stage IV disease.[Methods] 20 patients [14 men, 6 women, median age 67 (39-82) years] were observed after initial diagnosis of non-curatively resectable metastasized symptomatic (83 %) or asymptomatic (17 %) CRC, from June 2002 to April 2009. If necessary, endoscopic tumor debulking was performed. 5-FU based chemotherapy was given immediately thereafter. In 10 patients, chemotherapy was combined with antibody therapy.[Results] Response of the primary was observed in all patients. Local symptoms were treated endoscopically whenever necessary (obstruction or bleeding), and further improved after chemotherapy was started: Four patients showed initial complete endoscopic disappearance of the primary. In an additional 6 patients, only adenomatous tissue was histologically detected. In both these groups, two patients revealed local tumor relapse after interruption of therapy. Local tumor regression or stable disease was achieved in the remaining 10 patients. 15 patients died during the observation time. In 13 cases, death was related to metastatic disease progression. The mean overall survival time was 19.6 (3-71) months. No complications due to the primary were observed.[Conclusions] This study shows that modern anti-cancer drugs combined with endoscopic therapy are an effective and safe treatment of the symptomatic primary and ameliorate local complaints without the need for surgical intervention in advanced UICC stage IV CRC.

Prognostic relevance of Wnt-inhibitory factor-1 (WIF1) and Dickkopf-3 (DKK3) promoter methylation in human breast cancer

Jurgen Veeck — 2009-07-01T00:00:00Z

Background: Secreted Wnt signaling antagonists have recently been described as frequent targets of epigenetic inactivation in human tumor entities. Since gene silencing of certain Wnt antagonists was found to be correlated with adverse patient survival in cancer, we aimed at investigating a potential prognostic impact of the two Wnt antagonizing molecules WIF1 and DKK3 in breast cancer, which are frequently silenced by promoter methylation in this disease. Methods: WIF1 and DKK3 promoter methylation were assessed by methylation-specific PCR with bisulfite-converted DNA from 19 normal breast tissues and 150 primary breast carcinomas. Promoter methylation was interpreted in a qualitative, binary fashion. Statistical evaluations included two-sided Fisher's exact tests, univariate log-rank tests of Kaplan-Meier curves as well as multivariate Cox regression analyses. Results: WIF1 and DKK3 promoter methylation were detected in 63.3% (95/150) and 61.3% (92/150) of breast carcinoma samples, respectively. In normal breast tissues, WIF1 methylation was present in 0% (0/19) and DKK3 methylation in 5.3% (1/19) of samples. In breast carcinomas, WIF1 methylation was significantly associated with methylation of DKK3 (p = 0.009). Methylation of either gene was not associated with clinicopathological parameters, except for DKK3 methylation being associated with patient age (p = 0.007). In univariate analysis, WIF1 methylation was not associated with clinical patient outcome. In contrast, DKK3 methylation was a prognostic factor in patient overall survival (OS) and disease-free survival (DFS). Estimated OS rates after 10 years were 54% for patients with DKK3-methylated tumors, in contrast to patients without DKK3 methylation in the tumor, who had a favorable 97% OS after 10 years (p < 0.001). Likewise, DFS at 10 years for patients harboring DKK3 methylation in the tumor was 58%, compared with 78% for patients with unmethylated DKK3 (p = 0.037). Multivariate analyses revealed that DKK3 methylation was an independent prognostic factor predicting poor OS (hazard ratio (HR): 14.4; 95% confidence interval (CI): 1.9-111.6; p = 0.011), and short DFS (HR: 2.5; 95% CI: 1.0-6.0; p = 0.047) in breast cancer. Conclusions: Although the Wnt antagonist genes WIF1 and DKK3 show a very similar frequency of promoter methylation in human breast cancer, only DKK3 methylation proves as a novel prognostic marker potentially useful in the clinical management of this disease.