CXCR4 expression in papillary thyroid carcinoma: induction by nitric oxide and correlation with lymph node metastasis

<p>Abstract</p> <p>Background</p> <p>Metastasis to regional lymph nodes is a common step in the progression of cancer. Recent evidence suggests that tumor production of CXCR4 promotes lymph node metastasis. Nitric oxide (NO) may also increase metastatic ability in human cancers.</p> <p>Methods</p> <p>Nitrite/nitrate levels and functional CXCR4 expression were assessed in K1 and B-CPAP papillary thyroid carcinoma (PTC) cells after induction and/or inhibition of NO synthesis. CXCR4 expression was also analyzed in primary human PTC. The relationship between nitrotyrosine levels, which are a biomarker for peroxynitrate formation from NO in vivo, CXCR4 expression, and lymph node status was also analyzed.</p> <p>Results</p> <p>Production of nitrite/nitrate and functional CXCR4 expression in both cell lines was increased by treatment with the NO donor DETA NONOate. The NOS inhibitor L-NAME eliminated this increase. Positive CXCR4 immunostaining was observed in 60.7% (34/56) of PTCs. CXCR4 expression was significantly correlated with nitrotyrosine levels and lymph node metastasis in human PTC.</p> <p>Conclusion</p> <p>Our data indicate that NO stimulates CXCR4 expression in vitro. Formation of the NO biomarker nitrotyrosine was also correlated with CXCR4 expression and lymph node metastasis in human PTC. NO may induce lymph node metastasis via CXCR4 induction in papillary thyroid carcinoma.</p

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

<p>Abstract</p> <p>Background</p> <p>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).</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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 <it>in vitro</it>.</p

Successful Dasatinib Treatment of Epidermal Growth Factor Receptor-Mutant Lung Adenocarcinoma and BCR-ABL1-Positive Chronic Myeloid Leukemia: A Case Report

Dasatinib, a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI), inhibits multiple kinase pathways and is a promising anti-tumor agent for various solid tumors, including lung cancer. Herein, we report a patient with coexisting epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma and BCR-ABL1-positive chronic myeloid leukemia (CML). The patient received afatinib for a postoperative intrapulmonary recurrence of lung adenocarcinoma harboring EGFR exon 19 deletion. Tumor reduction was achieved with afatinib; however, dose reduction was required because of grade 2 diarrhea and skin toxicity. The reduced dose maintained a partial response. Thirty-one months after introduction of afatinib, he was diagnosed as having BCR-ABL1-positive CML and nilotinib was added to his treatment regimen. However, the combination of nilotinib and afatinib aggravated his diarrhea, prompting discontinuation of afatinib. Because nilotinib does not have sufficient anti-tumor efficacy for CML, dasatinib was substituted for nilotinib. Thirty-five months after introduction of dasatinib, bosutinib was substituted for dasatinib because of uncontrollable pleural effusions. Dasatinib achieved 31- and 35-month progression-free survivals for CML and EGFR-mutant lung adenocarcinoma, respectively. Dasatinib is thus a therapeutic option for coexisting EGFR-mutant lung adenocarcinoma and BCR-ABL1-positive CML when TKI combination therapy is contraindicated by severe adverse events. In our patient, adding nilotinib to afatinib led to severe diarrhea. When administering TKI combination therapy, drug-drug interactions should be considered

Signet ring cell carcinoma of the ampulla of vater: Report of a case and a review of the literature

Introduction: Signet ring cell carcinoma (SRCC) of the ampulla of vater is a very rare tumor that is reported infrequently in the literature. Presentation of case: A 59-year-old woman visited our hospital for evaluation of elevated transaminase levels. On laboratory examination of tumor marker levels, carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19–9 levels were normal, and DUPAN-2 was elevated. Computed tomography (CT) confirmed a 2 cm, enhanced mass in the periampullary region, with marked common bile duct dilatation. Endoscopic retrograde cholangiopancreatography (ERCP) showed a swollen papilla of vater, with a reddish, erosive mucosa. Histological examination of biopsy samples from the ampulla of vater showed signet ring cell carcinoma (SRCC). The patient underwent radical pancreatoduodenectomy. Pathological examination showed that the SRCC had infiltrated into the duodenal muscularis propria and pancreatic parenchyma, and lymph node metastases were identified around the abdominal aorta and common hepatic artery. Based on the immunohistochemical staining patterns of the positive results for CDX2 and MUC2, the tumor cells in the present case appeared to have an intestinal type origin. The ampullary cancer was diagnosed as T3bN1M1, Stage IV according to the International Union Against Cancer TNM classification (UICC). After undergoing adjuvant chemotherapy with cisplatin–gemcitabine chemotherapy for 6 months, the patient has remained disease-free in the 7 months since surgery. Discussion: SRCC of intestinal-type origin is associated with a favorable outcome. Conclusion: Investigation to confirm the histological origin of SRCC by immunohistochemical staining might inform the treatment strategy and identify patients with ampullary SRCC who may have a good prognosis