Stromal-derived factor-1α/CXCL12-CXCR4 chemotactic pathway promotes perineural invasion in pancreatic cancer

Perineural invasion (PNI) is considered as an alternative route for the metastatic spread of pancreatic cancer cells; however, the molecular changes leading to PNI are still poorly understood. In this study, we show that the CXCL12/CXCR4 axis plays a pivotal role in the neurotropism of pancreatic cancer cells to local peripheral nerves. Immunohistochemical staining results revealed that CXCR4 elevation correlated with PNI in 78 pancreatic cancer samples. Both in vitro and in vivo PNI models were applied to investigate the function of the CXCL12/CXCR4 signaling in PNI progression and pathogenesis. The results showed that the activation of the CXCL12/CXCR4 axis significantly increased pancreatic cancer cells invasion and promoted the outgrowth of the dorsal root ganglia. CXCL12 derived from the peripheral nerves stimulated the invasion and chemotactic migration of CXCR4-positive cancer cells in a paracrine manner, eventually leading to PNI. In vivo analyses revealed that the abrogation of the activated signaling inhibited tumor growth and invasion of the sciatic nerve toward the spinal cord. These data indicate that the CXCL12/CXCR4 axis may be a novel therapeutic target to prevent the perineural dissemination of pancreatic cancer.     

Hepatic microenvironment underlies fibrosis in chronic hepatitis B patients

BACKGROUND Chronic hepatitis B virus(HBV) infection is a leading cause of liver morbidity and mortality worldwide. Liver fibrosis resulting from viral infection-associated inflammation and direct liver damage plays an important role in disease management and prognostication. The mechanisms underlying the contribution of the liver microenvironment to fibrosis in HBV patients are not fully understood. There is an absence of effective clinical treatments for liver fibrosis progression; thus, establishing a suitable in vitro microenvironment in order to design novel therapeutics and identify molecular biomarkers to stratify patients is urgently required.AIM To examine a subset of pre-selected microenvironment factors of chronic HBV patients that may underlie fibrosis, with a focus on fibroblast activation.METHODS We examined the gene expression of key microenvironment factors in liver samples from patients with more advanced fibrosis compared with those with less severe fibrosis. We also used the human stellate cell line LX-2 in the in vitro study. Using different recombinant cytokines and growth factors or their combination, we studied how these factors interacted with LX-2 cells and pinpointed the crosstalk between the aforementioned factors and screened the most important factors.RESULTS Of the secreted factors examined, transforming growth factor(TGF)-β1, interleukin(IL)-1β and tumor necrosis factor(TNF)-α were increased in patients with advanced fibrosis. We found that besides TGF-β1, IL-1β can also induce a profibrotic cascade by stimulating the expression of connective tissue growth factor and platelet-derived growth factor(PDGF) in LX-2 cells. Furthermore, the proinflammatory response can be elicited in LX-2 cells following treatment with IL-1β and TNF-α, suggesting that stellate cells can respond to proinflammatory stimuli. By combining IL-1β and TGF-β1, we observed not only fibroblast activation as shown by αlpha-smooth muscle actin and PDGF induction, but also the inflammatory response as shown by increased expression of IL-1β.CONCLUSION Collectively, our data from HBV patients and in vitro studies demonstrate that the hepatic microenvironment plays an important role in mediating the crosstalk between profibrotic and proinflammatory responses and modulating fibrosis in chronic HBV patients. For the establishment of a suitable in vitro microenvironment for HBV-induced liver fibrosis, not only TGF-β1 but also IL-1β should be considered as a necessary environmental factor.     

SIBLINGs and SPARC families: Their emerging roles in pancreatic cancer

Pancreatic cancer has a considerably poor prognosis with a 5-year survival probability of less than 5% when all stages are combined. Pancreatic cancer is characterized by its dense stroma, which is involved in the critical interplay with the tumor cells throughout tumor progression and furthermore, creates a barrier restricting efficient penetration of therapeutics. Alterations in a large number of genes are reflected by a limited number of signaling pathways, which are potential targets. Understanding more about the molecular basis of this devastating cancer type regarding tumor microenvironment, distinct subpopulations of cells, epithelial-to-mesenchymal transition and inflammation will lead to the development of various targeted therapies for controlling tumor growth and metastasis. In this complex scenario of pancreatic cancer, especially members of the “small integrin binding ligand N-linked glycoproteins” (SIBLINGs) and “secreted protein acidic and rich in cysteine” (SPARC) families have emerged due to their prominent roles in properties including proliferation, differentiation, apoptosis, adhesion, migration, angiogenesis, wound repair and regulation of extracellular matrix remodeling. SIBLINGs consist of five members, which include osteopontin (OPN), bone sialoprotein, dentin matrix protein 1, dentin sialophosphoprotein and matrix extracellular phosphoglycoprotein. The SPARC family of modular extracellular proteins is comprised of SPARC/osteonectin (ON) and SPARC-like 1 (hevin); secreted modular calcium binding proteins; testicans and follistatin-like protein. In this review, we especially focus on OPN and ON, elaborating on their special and growing importance in pancreatic cancer diagnosis and prognosis.     

Lumican蛋白在胰腺导管腺癌间质中的表达及其与Ki-67、VEGF及突变型P53表达的相关性

目的:观察细胞外基质蛋白Lumican在胰腺导管腺癌(pancreatic ductal adenocarcinoma,PDA)中表达特征,分析Lumican与Ki-67、VEGF、突变型P53等肿瘤恶性表型相关分子的关联.方法:采用免疫组织化学染色(IHC)和逆转录-聚合酶链式反应(RT-PCR)检测PDA原发灶及对应癌旁胰腺组织中Lumican表达.IHC检测PDA原发灶Ki-67、VEGF及突变型P53表达.用SPSS软件行统计学分析.结果:PDA原发灶中,Lumican表达在mRNA及蛋白质水平均明显高于癌旁胰腺组织.就该蛋白在癌灶中的分布特性而言,Lumican蛋白主要定位于癌间质,阳性表达率为83.0%(83/100).低分化PDA中,癌间质过表达Lumican与TNM分期相关(x2=6.446,P<0.05),与年龄、性别、淋巴结转移、远处转移等无明显相关.高中分化PDA中,癌间质过表达Lumican与临床病理特征无关,而与Ki-67(r=-0.28,P=0.017)、VEGF(r=-0.264,P=0.025)及突变型P53(r=-0.253,P=0.032)表达呈明显负相关.结论:Lumican在PDA原发灶中表达高于癌旁胰腺组织,主要分布于癌间质.Lumican在癌间质过表达与低分化PDA的TNM分期相关,与高、中分化PDA的Ki-67、VEGF及突变型P53表达呈负相关.     

骨质疏松骨髓微环境的影像研究进展

骨质疏松是一种全身代谢性疾病,是一种以骨强度降低为特征,导致骨折易发的骨病。骨髓微环境是骨吸收和骨重建的重要场所。其中骨髓微环境中的脂肪细胞的增加、微血管数目的减少和微循环的障碍是骨质疏松发生、发展的重要因素。因此,研究骨髓脂肪含量及微循环变化在骨质疏松中的作用显得尤为重要。就骨髓微环境诸因素的影像研究进展进行综述。     

The Association of Intra-Tumoral and Stromal Vitamin D Receptor (VDR) Expressions with Molecular Subtypes and Clinicopathological Factors in Breast Carcinoma

Objective: This study aimed to investigate the association between intra-tumoral and stromal VDR expressions with molecular subtypes and clinicopathological factors. Methods: A total of 75 formalin-fixed paraffin embedded tissue samples were stained using immunohistochemical methods. The VDR expressions were measured by counting brown-stained nuclei in intra-tumoral and stromal areas. The association of VDR expression with molecular subtypes and clinopathological factors was examined. Statistical analysis was performed by chi square tests. Results: High intra-tumoral VDR expression was found in carcinomas with luminal molecular subtypes (p=0.039) and low histological degrees (p=0.035). High VDR expression in the stroma was found in breast carcinomas with large tumor sizes. Conclusions: High intra-tumoral VDR expression is found in breast carcinomas with luminal subtypes and low histological grade (I/II). Both factors are known to have a good prognosis. These findings further strengthen the function of VDR as anti-tumorigenesis.     

结肠癌细胞上清液对CD4~＋FOXP3~＋调节性T淋巴细胞形成影响

目的观察结肠癌细胞上清液是否能促进正常CD4＋T淋巴细胞转换成调节性T淋巴细胞,并且探讨TGFβ1在促细胞转换中的重要作用。方法应用流式细胞仪染色CD4＋FOXP3＋,ELISA检测结肠癌上清液中TGFβ1浓度。结果分选的CD4＋CD25-细胞纯度高达96.58%±0.59%,这群细胞中表达CD4＋FOXP3＋较低,为0.34%±0.03%。健康正常人CD4＋FOXP3-细胞分别与人结肠癌细胞colo320HSR及DLD-1上清液共培养后,CD4＋FOXP3＋细胞表达增高（colo320HSR组为4.78%±0.41%,DLD-1组为4.48%±0.29%）;这两组与RPMI 1640培养液阴性对照组CD4＋FOXP3＋细胞2.54%±0.41%相比差异有统计学意义（P〈0.05）。ELISA法检测colo320HSR细胞上清液TGFβ1浓度为（1 228.80±10.65）ng/mL,DLD-1细胞上清液TGFβ1浓度（624.50±12.26）ng/mL,而RPMI 1640无血清培养液中未检测到TGFβ1。在与结肠癌细胞上清液培养同时给与TGFβ抗体后,CD4＋FOXP3＋表达较未加入抗体组明显降低（colo320HSR组2.20%±0.09%,P=0.011;DLD-1组1.67%±0.34%,P=0.033）;而RPMI1640阴性对照组CD4＋FOXP3＋细胞表达下降不显著（1.80%±0.58%,P=0.159）。结论人结肠癌细胞上清液可以促进正常CD4＋T淋巴细胞（CD4＋FOXP3-细胞）转换为调节性T淋巴细胞（CD4＋FOXP3＋）,TGFβ1在肿瘤微环境中调节T淋巴细胞形成可能有一定的作用。识别人调节性T淋巴细胞（CD4＋FOXP3＋）的起源将为肿瘤治疗提供重要信息。