Expression and Prognostic Significance of CD151, c-Met, and Integrin alpha3/alpha6 in Pancreatic Ductal Adenocarcinoma

Zhu, Guijin; Huang, Chen; Qiu, Zhengjun; Lee, Jun; Zhang, Zhihua; Zhao, Ning; Feng, Zheng-zhong; Lv, Xiu-Hong

doi:10.1007/s10620-010-1416-x

Cited by 88 publications

(76 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Conversely, its abnormal stimulation, through overexpression (with or without gene amplification or mutations) or aberrant autocrine or paracrine HGF ligand production, mediates the activation of a wide range of different cellular signaling pathways involved in proliferation, scattering, and invasion (38). Accordingly, c-Met has been shown to be upregulated in many solid tumors, including PDAC (39,40), in which its stimulation has been associated with poor prognosis and chemoresistance (38,41). Moreover, it has been shown that c-Met plays a key role in the cancer/ stroma interaction (10), and is a marker for pancreatic cancer stem cells, representing an optimal target to prevent the development of metastases (42).…”

Section: Discussionmentioning

confidence: 99%

Crizotinib Inhibits Metabolic Inactivation of Gemcitabine in c-Met–driven Pancreatic Carcinoma

et al. 2013

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) remains a major unsolved health problem. Most drugs that pass preclinical tests fail in these patients, emphasizing the need of improved preclinical models to test novel anticancer strategies. Here, we developed four orthotopic mouse models using primary human PDAC cells genetically engineered to express firefly-and Gaussia luciferase, simplifying the ability to monitor tumor growth and metastasis longitudinally in individual animals with MRI and high-frequency ultrasound. In these models, we conducted detailed histopathologic and immunohistochemical analyses on paraffin-embedded pancreatic tissues and metastatic lesions in liver, lungs, and lymph nodes. Genetic characteristics were compared with the originator tumor and primary tumor cells using array-based comparative genomic hybridization, using frozen specimens obtained by laser microdissection. Notably, the orthotopic human xenografts in these models recapitulated the phenotype of human PDACs, including hypovascular and hypoxic areas. Pursuing genomic and immunohistochemical evidence revealed an increased copy number and overexpression of c-Met in one of the models; we examined the preclinical efficacy of c-Met inhibitors in vitro and in vivo. In particular, we found that crizotinib decreased tumor dimension, prolonged survival, and increased blood and tissue concentrations of gemcitabine, synergizing with a cytidine deaminase-mediated mechanism of action. Together, these more readily imaged orthotopic PDAC models displayed genetic, histopathologic, and metastatic features similar to their human tumors of origin. Moreover, their use pointed to c-Met as a candidate therapeutic target in PDAC and highlighted crizotinib and gemcitabine as a synergistic combination of drugs warranting clinical evaluation for PDAC treatment. Cancer Res; 73(22); 6745-56. Ó2013 AACR.

show abstract

Section: Discussionmentioning

confidence: 99%

Crizotinib Inhibits Metabolic Inactivation of Gemcitabine in c-Met–driven Pancreatic Carcinoma

et al. 2013

View full text Add to dashboard Cite

show abstract

“…For ITGA3, it has been established that α3β1 integrin is involved in the maintenance of basement membrane integrity through adhesion to laminin 5 and plays an essential role in the invasiveness and metastatic potential of tumor cells (30)(31)(32). However, there are contradictory reports regarding the significance of ITGA3 expression in various types of cancers (33)(34)(35)(36). Considering the results demonstrated recently that GAL3ST3 is involved in tumor metastasis by regulating the ability of adhesion to selectins and expression of integrins, more evidence is needed to clarify the relationship among these molecules (25).…”

Section: Discussionmentioning

confidence: 99%

DNA methylation status of a distinctively different subset of genes is associated with each histologic Lauren classification subtype in early gastric carcinogenesis

et al. 2014

View full text Add to dashboard Cite

Abstract. DNA methylation change is known to play a crucial role in early gastric carcinogenesis. The present study aimed to identify and validate the correlation between differentially methylated regions (DMRs) and the subtypes of early gastric cancers (EGCs). Illumina Infinium methylation assay (IIMA; 450K BeadChip kit) was performed on fresh tumor and non-tumor tissues of 12 EGCs to screen the methylation status of 450,000 CpG sites. To evaluate the significance of DNA methylation in each histologic subtype, pyrosequencing assay (PA) was performed on 38 EGCs (18 intestinal-, 12 mixed-and 8 diffuse-type) using 12 genes selected from the screening. Between tumors of the intestinal-type (n=6), and diffuse-(n=4) plus mixed-types (n=2), 169 regions showed significant differences (intensity >3,000, Δβ >0.2) in IIMA. Hierarchical clustering using the 169 DMRs revealed distinct separation between the two groups. In PA using 12 selected genes from the IIMA results, the aberrant methylation statuses of DVL2 (p=0.0186) and ETS1 (p=0.0222) were significantly related to diffuse-and mixed-types rather than the intestinal-type, while C19orf35 (p=0.019) and CNRIP1 (p=0.0473) were related to the diffuse-type rather than intestinal-type, and GAL3ST2 (p=0.0158) and ITGA3 (p=0.0273) were related to the mixedtype rather than the other two types. The methylation of other genes, CLIP4, XKR6, CCDC57, MAML3 and SDC2, was related with age, tumor location, or Helicobacter infection rather than the histologic subtype. Aberrant DNA methylation of certain genes may be independently involved in each histologic subtype of EGC. Furthermore, mixed-type EGCs may be a distinctive histologic subtype based on the different subset of DMRs compared to those of other subtypes. IntroductionDespite its decreasing trend, gastric cancer (GC) still remains one of the most troublesome malignant diseases worldwide. It is the fourth most common cancer and the second leading cause of cancer-related death worldwide (1-3). In Asian countries such as Japan and Korea, it has the highest incidence among all malignancies although its overall survival rate has improved during the last few decades due to extensive screening programs (3,4). Due to the poor prognosis and limited treatment options of advanced GC, it remains a challenging task to determine effective molecular-pathological markers for early diagnosis with appropriate histological classification (5).Lauren classification, which subgroups GCs mainly as two types, intestinal and diffuse, was first introduced in 1965 and has been generally accepted as a distinct and simple histological classification of GCs by most pathologists (6). Since the two major types show distinctively different phenotypic, epidemiologic and biologic characteristics, it is believed that different genetic alterations may be implicated in each histologic type of the classification (7). However, a considerable number of GCs accounting for 10-15% of cases, share the histologic features of these two types and are designated as mixed-type ...

show abstract

“…Clinically, high levels of CD151 are correlated with poor prognosis in a variety of tumours including epithelial malignancies such as carcinomas of the lung, 68 breast (invasive ductal carcinoma), 34,53,69 colon, 70 pancreas, 71 kidney, 10 prostate (PCa), 72 liver 73,74 and oesophagus (SCC), 75 as well as glioblastoma. 76 As in most cancers an elevated level of CD151 expression is associated positively with a high tumour grade (Table 1), the assumption that CD151 is involved in cancer progression is well grounded.…”

Section: Clinical Aspects Of Cd151 Expressionmentioning

confidence: 99%

“…Indeed, overexpression of CD151 at the primary site was found to correspond with the development of metastases, mostly in lymph nodes. 53,71,[73][74][75] Formation of secondary tumours in distant organs such as lungs and bone was also noted in clear cell renal carcinoma (RCC). 10 CD151 is implicated as a potential diagnostic marker in osteosarcoma and prostate cancer.…”

Section: Clinical Aspects Of Cd151 Expressionmentioning

confidence: 99%

CD151 in cancer progression and metastasis: a complex scenario

Sądej

Grudowska

Turczyk

et al. 2014

Laboratory Investigation

View full text Add to dashboard Cite

Originally identified as a molecular organizer of interacting proteins into tetraspanin-enriched microdomains, the tetraspanin CD151 has now been shown to be involved in tumour progression. Increasing evidence emerging from in vitro, in vivo and clinical analyses implicates this tetraspanin in supporting growth of various types of tumours at different levels. It affects both cell autonomous behavior and communication with neighboring cells and the microenvironment. CD151 regulates post-adhesion events, that is, cell spreading, migration and invasion including subsequent intravasation and formation of metastasis. Present on both neoplastic and endothelial cells, CD151 is engaged in promotion of tumour neovascularization. The molecular mechanism of CD151 in cancer is based on its ability to organize distribution and function of interacting proteins, ie, laminin-binding integrins (a3b1, a6b1 and a6b4), receptors for growth factors (HGFR, EGFR and TGF-b1R) and matrix metalloproteinases (MMP-7, MMP-2 and MMP-9), which indicates its importance in disease development. Results of clinical analyses of CD151 expression in different types of cancer and a large number of in vivo models demonstrate its impact on tumour growth and invasion and implicate CD151 as a valuable diagnostic and prognostic marker as well as a potential target for anti-cancer therapy. INTRODUCTIONTumour cells progress through multiple orchestrated steps before metastatic lesions are established in distant organs. These steps include detachment from the primary tumour mass, invasion of the basement membrane, migration through the surrounding extracellular matrix (ECM) followed by intravasation and extravasation and, finally, colonization of a secondary anatomical site. Successful completion of this sequence requires intrinsic changes enabling phenotypic transformation of the cell and, at every step, its coordinated communication with the tumour's microenvironment. A complex network of intricate tumourstroma interactions involves integrin-dependent adhesion and cell migration on the ECM, ECM degradation by matrix metalloproteinases (MMPs), and activation of signalling pathways responsible for cell survival, proliferation and motility, triggered by growth factor receptors stimulated by the environment.

show abstract

Expression and Prognostic Significance of CD151, c-Met, and Integrin alpha3/alpha6 in Pancreatic Ductal Adenocarcinoma

Abstract: CD151, c-Met, and integrin alpha3/alpha6 were all overexpressed in PDAC. CD151 and c-Met might be new molecular markers to predict the prognosis of PDAC patients.

Cited by 88 publications

References 44 publications

Crizotinib Inhibits Metabolic Inactivation of Gemcitabine in c-Met–driven Pancreatic Carcinoma

Crizotinib Inhibits Metabolic Inactivation of Gemcitabine in c-Met–driven Pancreatic Carcinoma

DNA methylation status of a distinctively different subset of genes is associated with each histologic Lauren classification subtype in early gastric carcinogenesis

CD151 in cancer progression and metastasis: a complex scenario

Contact Info

Product

Resources

About