Japanese Foundation for Cancer Research

About: Japanese Foundation for Cancer Research is a nonprofit organization based out in Tokyo, Japan. It is known for research contribution in the topics: Cancer & Breast cancer. The organization has 2676 authors who have published 5482 publications receiving 221859 citations.

EMT-Induced Stemness and Tumorigenicity Are Fueled by the EGFR/Ras Pathway

Abstract: Recent studies have revealed that differentiated epithelial cells would acquire stem cell-like and tumorigenic properties following an Epithelial-Mesenchymal Transition (EMT). However, the signaling pathways that participate in this novel mechanism of tumorigenesis have not been fully characterized. In Runx3−/−p53−/− murine gastric epithelial (GIF-14) cells, EMT-induced plasticity is reflected in the expression of the embryonal proto-oncogene Hmga2 and Lgr5, an exclusive gastrointestinal stem cell marker. Here, we report the concurrent activation of an EGFR/Ras gene expression signature during TGF-β1-induced EMT in GIF-14 cells. Amongst the altered genes was the induction of Egfr, which corresponded with a delayed sensitization to EGF treatment in GIF-14. Co-treatment with TGF-β1 and EGF or the expression of exogenous KRas led to increased Hmga2 or Lgr5 expression, sphere initiation and colony formation in soft agar assay. Interestingly, the gain in cellular plasticity/tumorigenicity was not accompanied by increased EMT. This uncoupling of EMT and the induction of plasticity reveals an involvement of distinct signaling cues, whereby the EGFR/Ras pathway specifically promotes stemness and tumorigenicity in EMT-altered GIF-14 cells. These data show that the EGFR/Ras pathway requisite for the sustenance of gastric stem cells in vivo and in vitro is involved in the genesis and promotion of EMT-induced tumor-initiating cells.

Arctigenin blocks the unfolded protein response and shows therapeutic antitumor activity.

Abstract: Cancer cells in poorly vascularized solid tumors are constantly or intermittently exposed to stressful microenvironments, including glucose deprivation, hypoxia, and other forms of nutrient starvation. These tumor-specific conditions, especially glucose deprivation, activate a signaling pathway called the unfolded protein response (UPR), which enhances cell survival by induction of the stress proteins. We have established a screening method to discover anticancer agents that could preferentially inhibit tumor cell viability under glucose-deprived conditions. Here we identify arctigenin (ARC-G) as an active compound that shows selective cytotoxicity and inhibits the UPR during glucose deprivation. Indeed, ARC-G blocked expression of UPR target genes such as phosphorylated-PERK, ATF4, CHOP, and GRP78, which was accompanied by enhanced phosphorylation of eIF2α during glucose deprivation. The UPR inhibition led to apoptosis involving a mitochondrial pathway by activation of caspase-9 and -3. Furthermore, ARC-G suppressed tumor growth of colon cancer HT-29 xenografts. Our results demonstrate that ARC-G can be served as a novel type of antitumor agent targeting the UPR in glucose-deprived solid tumors. J. Cell. Physiol. 224:33–40, 2010 © 2010 Wiley-Liss, Inc.

Laparoscopy-Assisted Pylorus-Preserving Gastrectomy with Quality Controlled Lymph Node Dissection in Gastric Cancer Operation

Abstract: Background Pylorus-preserving gastrectomy (PPG) with extensive lymph node dissection is useful for treatment of early gastric cancer with preservation of function. This technique could be improved by using laparoscopy-assisted gastrectomy. Study design Between September 2000 and September 2004, 109 patients with T1 gastric cancer underwent surgical treatment; 72 underwent laparoscopy-assisted PPG (LAPPG) and 37 underwent conventional PPG (CPPG). Total numbers of dissected lymph nodes, retrieval at each lymph node station, intraoperative blood loss, and operation times were used as measures of the quality of lymph node dissection to compare the procedures. Continuous data are summarized as mean ± SE. Results Operation times with the LAPPG procedure (279 ± 6 minutes) were significantly, but only 20 minutes, longer than with CPPG (259 ± 8 minutes) (p = 0.047), although estimated blood loss for LAPPG patients (153 ± 13 mL) was not significantly different for those undergoing CPPG (184 ± 13 mL, p=0.13). Mean total number of dissected lymph nodes was 32.3 ± 1.6 in the LAPPG group and 28.5 ± 2.2 in the CPPG group (p = 0.16). There was no significant difference in the number of lymph nodes retrieved for any of the nodal stations between the LAPPG and CPPG procedures. Conclusions Clinical outcomes of surgical treatment were comparable for gastric cancer patients who underwent LAPPG and those treated with CPPG in terms of station-dependent lymph node dissection and estimated blood loss.

High concordance rate of KRAS/BRAF mutations and MSI-H between primary colorectal cancer and corresponding metastases

Abstract: Genetic testing is needed for the treatment of colorectal cancer (CRC), especially molecular-targeted therapy. The effects of anti-EGFR therapy and prognosis are affected by the presence of KRAS mutations. However, whether primary CRC or metastatic tissues are appropriate in the analysis is still unclear. In the present study, we assessed the concordance of KRAS/BRAF mutation status and microsatellite instability (MSI) in primary CRC and corresponding metastases. This study enrolled 457 patients with surgically resected primary and corresponding metastatic CRC (499 synchronous metastases and 57 metachronous metastases) and seven local recurrences, and KRAS/BRAF mutation and MSI status were analysed for these tumours. The concordance rates of KRAS mutation, BRAF mutation, wild-type, MSI-H and MSS between primary CRC and corresponding metastases were 93.9% (214/228), 100% (30/30), 99.3% (304/306), 87.5% (21/24) and 100% (137/137), respectively. These high concordance rates were not different between synchronous and metachronous metastases. In conclusion, a high concordance of KRAS/BRAF mutation status and MSI status was observed between primary CRC and corresponding metastases in this study. Either primary CRC or metastatic tissues can be used for testing KRAS/BRAF mutation status and MSI status.

Platelet-activating factor podoplanin: from discovery to drug development

Abstract: Tumor cell-induced platelet aggregation facilitates hematogenous metastasis by promoting tumor embolization, preventing immunological assaults and shear stress, and the platelet-releasing growth factors support tumor growth and invasion. Podoplanin, also known as Aggrus, is a type I transmembrane mucin-like glycoprotein and is expressed on wide range of tumor cells. Podoplanin has a role in platelet aggregation and metastasis formation through the binding to its platelet receptor, C-type lectin-like receptor 2 (CLEC-2). The podoplanin research was originally started from the cloning of highly metastatic NL-17 subclone from mouse colon 26 cancer cell line and from the establishment of 8F11 monoclonal antibody (mAb) that could neutralize NL-17-induced platelet aggregation and hematogenous metastasis. Later on, podoplanin was identified as the antigen of 8F11 mAb, and its ectopic expression brought to cells the platelet-aggregating abilities and hematogenous metastasis phenotypes. From the 8F11 mAb recognition epitopes, podoplanin is found to contain tandemly repeated, highly conserved motifs, designated platelet aggregation-stimulating (PLAG) domains. Series of analyses using the cells expressing the mutants and the established neutralizing anti-podoplanin mAbs uncovered that both PLAG3 and PLAG4 domains are associated with the CLEC-2 binding. The neutralizing mAbs targeting PLAG3 or PLAG4 could suppress podoplanin-induced platelet aggregation and hematogenous metastasis through inhibiting the podoplanin-CLEC-2 binding. Therefore, these domains are certainly functional in podoplanin-mediated metastasis through its platelet-aggregating activity. This review summarizes the platelet functions in metastasis formation, the role of platelet aggregation-inducing factor podoplanin in pathological and physiological situations, and the possibility to develop podoplanin-targeting drugs in the future.