Purpose and Study Design: Recent studies have shown that β-catenin translocated into the cell nucleus functions like an oncogene. Accumulating evidence
suggests that activation of the β-catenin ...oncogenic signaling cascade along with its twin, the K- ras cascade, may exert syngeneic or synergistic effects on tumor development and progression. In the study reported here, we
analyzed oncogenic β-catenin activation on the basis of its nuclear accumulation (NA) and compared the results with those
of mutational activation of K- ras in 74 patients with colorectal cancer to determine whether the two oncogene-mediated signaling cascades interact.
Results: We found two distinct patterns of β-catenin activation, i.e. , diffuse NA in 20 cases (27%) and selective NA at the tumor invasion front (NAinv) in 19 cases (26%). The presence of the
NAinv pattern was significantly correlated with advanced Dukes’ stage tumor ( P = 0.0005) and the presence of distant metastases ( P = 0.0064). K- ras proto-oncogene was mutated in the tumors of 31 cases (42%). Activated β-catenin or K- ras was detected in most (78%) colorectal cancers analyzed, although a weak inverse correlation was found between the activities
of the two oncogenes in the tumors. Importantly, most (7 of 8) patients with tumor showing both K- ras activation and the NAinv pattern of β-catenin activation were in Dukes’ stage C at surgery, and half of them developed distant
metastases to the liver and lungs.
Conclusion : The results suggest that although oncogenic activation of β-catenin and K- ras is independent in the process of clinical cancer development, combined analysis of the two major oncogenes can detect most
colorectal cancers and identify a subset of patients with poorer outcomes. Consequently, activation of either or both of these
oncogenes may serve as a genetic marker for molecular diagnosis.
We report a patient with advanced esophageal cancer who achieved a complete response to combination chemotherapy of TS-1, docetaxel and CDDP. A 74-year-old man was admitted to our hospital for ...advanced esophageal cancer with a complaint of dysphagia. He received chemotherapy, consisting of TS-1 100 mg/body, docetaxel 35 mg/m(2), and CDDP 10 mg/m(2), every 3 weeks. TS-1 was administered for 14 days followed by 7 days rest; docetaxel and CDDP were administered by intravenous infusion at day one and day 8 after beginning TS-1. After three cycles of chemotherapy, his dysphagia disappeared, and endoscopic examination of the primary esophageal tumor showed a complete response. Endoscopic examination with biopsy confirmed the disappearance of the esophageal cancer. No severe side effects were observed during this chemotherapy. Combination chemotherapy of TS-1, docetaxel, and CDDP can thus be effective for advanced esophageal cancer.
Hereditary nonpolyposis colorectal cancer kindreds are frequently associated with cancers in various organs, including endometrium, stomach, and ovary. However, hematologic malignancy has rarely been ...reported in association with this cancer syndrome. We present here the case of a probable hereditary nonpolyposis colon cancer patient in whom non-Hodgkin's lymphoma developed after curative resection of colon cancer. Our experience with this rare case encouraged us to review the literature for reports indicating a possible relationship between these diseases.
A 52-year-old male whose family history was consistent with the criteria for hereditary nonpolyposis colon cancer underwent right hemicolectomy for ascending colon cancer. Histologically the tumor consisted of adenocarcinoma that was moderately differentiated with mucinous foci and that invaded beyond the muscularis propria. Neither metastasis nor lymphoma was found in paracolonic lymph nodes. Eight months after surgery, the patient developed non-Hodgkin's lymphoma of T-cell origin involving the ileum and lungs. Both colon cancer and lymphoma frequently showed microsatellite DNA instability, sharing alteration in a locus of chromosome 7 (D7S501).
A possible association of hematologic malignancy with hereditary nonpolyposis colon cancer reported in the literature, together with a report that MSH2-deficient mice are susceptible to malignant lymphoma, strongly supports the finding that this patient's lymphoma was related to hereditary nonpolyposis colon cancer. Overall, this case manifested a distinct clinical course similar to that observed in an animal model that is deficient in DNA mismatch repair machinery, thus providing scientific and clinical implications for understanding the molecular basis of these tumors and for critical management of hereditary nonpolyposis colorectal cancer patients, respectively.
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KISLJ, NUK, OILJ, PNG, SAZU, UL, UM, UPUK
In the realm of rare cardiac tumors, intimal sarcoma presents a formidable challenge, often requiring innovative treatment approaches. This case report presents a unique instance of primary intimal ...sarcoma in the left atrium, underscoring the critical role of genomic profiling in guiding treatment. Initial genomic testing unveiled a somatic, active mutation in PDGFRβ (PDGFRβ N666K), accompanied by MDM2 and CDK4 amplifications. This discovery directed the treatment course toward pazopanib, a PDGFRβ inhibitor, following irradiation. The patient's response was remarkable, with the therapeutic efficacy of pazopanib lasting for 16.3 months. However, the patient experienced a recurrence in the left atrium, where subsequent genomic analysis revealed the absence of the PDGFRβ N666K mutation and a significant reduction in PDGFRβ expression. This case report illustrates the complexities and evolving nature of cardiac intimal sarcoma treatment, emphasizing the potential of PDGFRβ signaling as a strategic target and highlighting the importance of adapting treatment pathways in response to genetic shifts.
Abstract Background and aims. We investigated expression of E-cadherin, β-catenin, and c-erbB-2 in gastric cancer to identify molecular factor(s) relevant to development of liver metastasis, which is ...a frequent cause of mortality in gastric cancer patients. Patients and methods. We analyzed by immunohistochemistry and compared expression patterns of E-cadherin, β-catenin, and c-erbB-2 in the tumor between 40 cases of gastric cancer (GC) without (GC-H-) and 16 with concurrent liver metastasis (GC-H+). Results. Loss of E-cadherin expression in the primary tumor was found in 18% of GC-H- and in 19% of GC-H+. Oncogenic β-catenin activation, represented by its nuclear translocation, was detected in 13% of GC-H- and in 31% of GC-H+. There was no statistical difference in incidence of alteration in these molecules between the two groups of patients. c-erbB-2 overexpression was more frequently observed in GC-H+ (10/16, 63%) than in GC-H- (5/40, 13%) while the distribution of histological types of the tumors was similar in the two groups of patients. This overexpression was also detected in metastatic liver tumors and biopsy specimens in the ten of the former group of patients. Conclusion. Our results strongly suggest a role of activated c-erbB-2 in the process of liver metastasis, and an importance of detection of this overexpression in biopsy specimens to identify GC patients who are at high risk of developing liver metastasis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The ubiquitin-proteasome pathway is important in regulating protein signaling pathways that are involved in tumorigenesis. beta-transducin repeat-containing proteins (beta-TrCP) are components of the ...ubiquitin ligase complex targeting beta-catenin and IkappaBalpha for proteasomal degradation and are thus a negative regulator of Wnt/beta-catenin signaling and a positive regulator of NF-kappaB signaling. We analyzed expression of beta-TrCP in colorectal cancers and its association with types of beta-catenin subcellular localization, an indirect measure of activation.
Levels of beta-TrCP1 mRNA and protein were measured by quantitative reverse transcription-polymerase chain reaction and immunoblotting, respectively, in samples of tumor and normal tissues from 45 patients with colorectal cancer. Types of beta-catenin activation (diffuse or invasion edge) and NF-kappaB activation were examined by immunohistochemistry. Apoptosis was determined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) assay. All statistical tests were two-sided.
Compared with the beta-TrCP1 levels in normal tissues, 25 (56%) of 45 tumors had increased beta-TrCP1 mRNA and protein levels. Of the 22 (49%) tumors with beta-catenin activation, 12 had the diffuse type (i.e., nuclear accumulation throughout the tumor) and 10 had the invasion edge type (i.e., nuclear accumulation predominantly in the tumor cells that formed the invasion edge). Increased beta-TrCP1 levels were statistically significantly associated with beta-catenin activation (P =.023) and decreased apoptosis (P =.035). beta-TrCP accumulated in the nuclei of tumor cells that contained increased levels of beta-TrCP1 mRNA and the active form of NF-kappaB. Higher levels of beta-TrCP1 mRNA were detected in primary tumors of patients who had metastases (0.960 arbitrary units, 95% confidence interval = 0.878 to 1.042) than in the tumors of patients who did not (0.722 arbitrary units, 95% confidence interval = 0.600 to 0.844; P =.016).
In colorectal cancer, increased expression of beta-TrCP1 is associated with activation of both beta-catenin and NF-kappaB, suggesting that the integration of these signaling pathways by increased beta-TrCP expression may contribute to an inhibition of apoptosis and tumor metastasis.
To find out whether p53 overexpression correlates with metastatic potential and other adverse prognostic factors in early invasive colorectal carcinoma and whether measurement of the expression of ...p53 protein could be helpful in the choice of treatment (endoscopic/local or radical resection).
Retrospective study.
University hospital, Japan.
Overexpression of p53 protein in the primary tumour was examined immunohistochemically in 50 patients with early invasive colorectal cancer.
Differences in p53 overexpression between subgroups.
Abnormal accumulation of nuclear p53 was detected in the primary tumour of 20 patients (40%) with early invasive colorectal cancer. We found p53-positive cells in 7 (78%) of 9 that had metastasised to regional lymph nodes or distant organs, or both, and in 13 (32%) of 41 that had not metastasised (p = 0.02). p53 Immunoreactivity was also present in 10 (71%) of 14 superficial (type II) lesions compared with 10 (28%) of 36 protruding (type I) ones (p = 0.009) and in 12 (57%) of 21 moderately differentiated adenocarcinomas compared with 8 (28%) of 29 well-differentiated adenocarcinomas (p = 0.045). There was no significant correlation between p53 overexpression and the depth of tumour invasion or angiolymphatic involvement. The p53-positive metastasising tumours had features that corresponded to those of early carcinoma arising de novo.
Our results seem to support the postulate that p53 overexpression in early invasive colorectal carcinomas is associated with an increase in their metastatic potential.
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