Clinical impacts of mesothelin expression in gastrointestinal carcinomas

Mesothelin,C-ERC/mesothelin is a 40-kD a cell surface glycoprotein that is normally present on normal mesothelial cells lining the pleura,peritoneum,and pericardium.Moreover,mesothelin has been shown to be overexpressed in several human cancers,including virtually all mesothelioma and pancreatic cancer approximately 70% of ovarian cancer and extra bile duc cancer,and 50% of lung adenocarcinomas and gastric cancer.The full-length human mesothelin gene encodes the primary product,a 71-k Da precursor protein.The71-kD a mesothelin precursor is cleaved into two products40-k Da C-terminal fragment that remains membranebound via glycosylphosphatidylinositol anchor,and a31-kD a N-terminal fragment,megakaryocyte potentiating factor,which is secreted into the blood.The biologica functions of mesothelin remain largely unknown However,results of recent studies have suggested tha the mesothelin may play a role of cell proliferation and migration.In pancreatic cancer,mesothelin expression was immunohistochemically observed in all cases,bu absent in normal pancreas and in chronic pancreatitis Furthermore,the expression of mesothelin was correlated with an poorer patient outcome in severa human cancers.The limited mesothelin expression in normal tissues and high expression in many cancers makes it an attractive candidate for cancer therapy.The present review discusses the expression and function o mesothelin in cancer cells and the utility of mesothelin as a target of cancer therapy.

Crk adaptor protein-induced phosphorylation of Gab1 on tyrosine 307 via Src is important for organization of focal adhesions and enhanced cell migration

在生长因素刺激之上，支架蛋白质， Gab1，是酷氨酸 phosphorylated 并且随后适配器蛋白质， Crk，从 Gab1 播送信号。我们以前证明了没有细胞外的刺激， Crk overexpression，在各种各样的人的癌症可检测，导致 Gab1 的酷氨酸 phosphorylation。在现在的学习，内在的机制进一步被调查。CrkII 的 Mutational 分析证明 SH2 领域，然而并非 SH3 (N) 或 CrkII 的规章的 Y221 残余，为 Gab1-Y307 phosphorylation 的正式就职是批评的。CrkII 的 SH2 变化也减少了和 Gab1 的相互作用。在 GST 下拉试金，而 Crk-SH3 (N) 与 Gab1 异种交往了， Crk-SH2 跳了到野类型的 Gab1，它缺乏聚类的酷氨酸区域(残余 242-410 ) 。Gab1 的酷氨酸 phosphorylation 被表明适配器的所有 Crk 家庭蛋白质，然而并非另外的包含 SH2 导致。Src 家庭 kinase 禁止者， PP2，废除 Gab1 的导致 Crk 的酷氨酸 phosphorylations。Y307 phosphorylation 在缺乏 Src，是，和 Fyn 的成纤维细胞是无法发现的，甚至在 Crk 的 overexpression 之上，而缺乏仅仅是和 Fyn 的房间仍然与 phosphorylated Y307 包含了 Gab1。而且， Crk 导致了 Src-Y416 的 phosphorylation；因此，在 Crk 和 Csk 之间的相互作用被增加。Gab1-Y307F 异种没能近甚至在 HGF 之上本地化血浆膜刺激和减少的房间移植。而且， Gab1-Y307F 扰乱了 Crk， FAK，和 paxillin 的本地化，它是焦点的粘附的典型部件。一起拿，这些结果显示 Crk 通过 Src 便于 Gab1-Y307 的酷氨酸 phosphorylation，贡献焦点的粘附和提高的房间移植的组织，可能从而支持人的癌症开发。

A novel GPCR mediates pancreatic cancer associated fibroblast-cancer cell interaction

OBJECTIVE Pancreatic ductal adenocarcinoma(PDAC),a lethal cancer in need of new,effective therapies,has a unique tumor microenvironment characterized by a dense fibrotic stroma(desmoplasia)that is generated by pancreatic cancer-associated fibroblasts(PCAFs)derived from pancreatic stellate cells(PSCs)and pancreatic fibroblasts(PFs).METHEDS and RESULTS Hypothesizing that G protein-coupled receptors(GPCRs)may regulate PCAFs,we used an unbiased GPCRomic array approach to compare GPCR expression in PCAFs,PFs and PSCs and identified 82 GPCRs commonly expressed by PCAFs derived from primary tumors of five PDAC patients.We discovered that PCAFs have increased expression of numerous GPCRs,in particular a GPCR with much higher expression in PCAFs compared to both PFs and PSCs.Immunohistochemistry revealed increased expression of this GPCR in PDAC tumors.Co-culture of PSCs with PDAC cells or incubation with TNFαinduced its expression.Activation of the GPCR in PCAF sincreased expression of interleukin-6(IL-6)via a cA MP/PKA/CREB signaling pathway.GPCR knockdown with siR NA diminished IL-6 production and secretionby PCAFs and ability of PCAF conditioned media to enhance proliferation of PDAC cells.CONCLUSION We conclude that PDAC cells induce expression by PCAFs of a novel GPCR,resulting in increased IL-6 production by PCAFs and promotion of PDAC cell proliferation.This PCAF-expressed GPCR thus contributes to PDAC cell-PCAF interaction and as such,may be a novel therapeutic target for PDAC tumors.

The first Japanese case of intraductal cancer of the prostate with checkpoint kinase 2 mutation

Dear editor:Intraductalcarcinomaoftheprostate(IDC-P)ischaracterized by expansive growth of cancer cells in normal prostatic ducts with basal cell layer and associated with high grade invasive prostate cancer(PCa).However,the molecular profile or clinical character of IDC-P in progressive castration-resistant PCa(CRPC)was not fully characterized yet.

Pancreatic Carcinoma with Prominent Mucin Production: A Clinicopathologic and Immunohistochemical Study of 9 Cases

Pancreatic carcinoma occasionally associated with prominent mucin production and this type of tumor designated as PCM (pancreatic carcinoma with prominent mucin production) was diagnosed depends on subjective estimation of the amount of mucous area, and there has been no report on a quantitative evaluation of the amount of mucinous area in the tumor. To examine the feature of PCM, we analyzed 9 cases of PCM among 243 cases of pancreas carcinoma and evaluated the amount of mucin by imaging analysis. Morphologically, 5 cases were classified as intradactal papillary mucinous neoplasms (IPMN)-derived PCM and 4 cases were as ductal adenocarcinoma (DA)-derived PCM. Mucous composition was found to be more than 50% in all IPMN-derived PCM cases, and that was 40% - 50% in DA-derived PCM cases with one exception. IPMN-derived PCM cases showed expansive growth with pancreatic duct dilatation filled with mucin, while DA-derived PCM cases possessed mucin infiltration into interstitial tissue. Immunohisto-chemically, three of 4 DA-derived PCM cases were MUC1(–)/MUC2(+), and the results of expressions for p16 and Dpc4 suggesting that DA-derived PCM was similar to IPMN-derived PCM rather than ordinary DA. Survival rate of DA-derived PCM cases was lower than that of IPMN-derived PCM cases. We advocate that DA-derived PCM may constitute a borderline group between IPMN and ordinary DA.

Germline BRCA2 mutation in a case of aggressive prostate cancer accompanied by spinal bulbar muscular atrophy

Dear Editor,Spinal and bulbar muscular atrophy(SBMA)or Kennedy’s disease is a rare X-linked,recessive,lower motor neuron disease caused by a CAG repeat expansion within the first exon of the androgen receptor(AR)gene.Instability of the CAG-triplet repeat impacts AR function;therefore,men with SBMA are thought to be at a very low risk of prostate cancer.We previously reported a case of high-risk prostate cancer with SBMA(repeat length 46).