Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix

During the process of tumor progression, cancer cells can produce the requisite growth- and invasion-promoting factors and can also rely on noncancerous cells in the tumor microenvironment as an alternative, cell-extrinsic source. However, whether the cellular source influences the function of such tumor-promoting factors remains an open question. Here, we examined the roles of the cathepsin Z (CtsZ) protease, which is provided by both cancer cells and macrophages in pancreatic neuroendocrine tumors in humans and mice. We found that tumor proliferation was exclusively regulated by cancer cell-intrinsic functions of CtsZ, whereas tumor invasion required contributions from both macrophages and cancer cells. Interestingly, several of the tumor-promoting functions of CtsZ were not dependent on its described catalytic activity but instead were mediated via the Arg–Gly–Asp (RGD) motif in the enzyme prodomain, which regulated interactions with integrins and the extracellular matrix. Together, these results underscore the complexity of interactions within the tumor microenvironment and indicate that cellular source can indeed impact molecular function.     

A novel tissue engineered three-dimensional in vitro colorectal cancer model

The interactions of cancer cells within a solid mass with the surrounding reactive stroma are critical for growth and progression. The surrounding vasculature is recruited into the periphery of the growing tumour to supply cancer cells with nutrients and O₂. This study focuses on developing a novel three-dimensional (3-D) in vitro biomimetic colorectal cancer model using colorectal cancer cells and connective tissue cells. The 3-D model comprises a dense artificial cancer mass, created by partial plastic compression of collagen type I containing HT29 colorectal cancer cells, nested in a non-dense collagen type I gel populated by fibroblasts and/or endothelial cells. HT29 cells within the dense mass proliferate slower than when cultured in a two-dimensional system. These cells form tumour spheroids which invade the surrounding matrix, away from the hypoxic conditions in the core of the construct, measured using real time O₂ probes. This model is also characterized by the release of vascular endothelial growth factor (VEGF) by HT29 cells, mainly at the invading edge of the artificial cancer mass. This characterization is fundamental in establishing a reproducible, complex model that could be used to advance our understanding of cancer pathology and will facilitate therapeutic drug testing.     

CLCA1在结肠癌组织中的表达及临床意义

目的:探讨CLCA1在结肠癌组织中的表达水平及其与肿瘤进展和预后的关系。方法:随机选取西安交通大学第一附属医院及第四军医大学西京医院行手术切除的临床结肠癌病例239例，应用免疫组织化学方法检测结肠癌组织及癌旁组织中CLCA1的表达情况，使用统计学方法分析CLCA1在结肠癌中的表达与肿瘤临床病理特征及预后的相关性。结果:CLCA1 在肿瘤中的表达较癌旁组织显著降低（P＜0.05），CLCA1在结肠癌中表达与原发肿瘤浸润深度、淋巴转移和肿瘤TNM分期显著相关（P＜0.05），而且CLCA1低表达组患者总体生存期较高表达组显著缩短（P＜0.001），多因素分析显示CLCA1的表达可作为结肠癌的独立预后因素。结论:CLCA1在结肠癌中表达下调，CLCA1的低表达与肿瘤的侵袭转移和临床预后密切相关，有望作为结肠癌个体化治疗靶点。     

S100A14, a mediator of epithelial-mesenchymal transition,regulates proliferation,migration and invasion of human cervical cancer cells

S100A14 is an EF-hand calcium-binding protein that has been reported to exert its biological effects on different types of cells. However, the potential clinical significance and biological functions of S100A14 in cervical cancer has not yet been clarified. In this study, we firstly examined the correlation between S100A14 expression and clinical-pathological parameters in cervical cancers. Next, we observed the effect of S100A14 on cell cycle progression, cell proliferation, migration and invasion by employing lentiviral-mediated overexpression and knockdown of S100A14 in cervical cancer cells. Furthermore, we investigated the underlying mechanism of S100A14 affecting cell migration and invasion. Immunohistochemistry analysis demonstrated that S100A14 expression was associated with the International Federation of Gynecology and Obstetrics (FIGO) stage (P = 0.025) and lymph node (LN) metastasis (P = 0.001). Functional assays showed that S100A14 overexpression increased the proportion of G2/M phase, promoted cell proliferation, migration, and invasion, whereas S100A14 knockdown exhibited adverse effect on above properties. Mechanistic investigation demonstrated that S100A14 can act as a mediator of epithelial-mesenchymal transition (EMT). And overexpression of S100A14 increased expression of N-cadherin and Vimentin while decreased expression of E-cadherin. The opposite results were observed in S100A14-silenced cells. Taken together, our data indicate that S100A14 has a crucial role in cervical cancer progression. This study significantly increases our understanding of S100A14 functional roles in cervical cancer, which may lead to the development of a novel therapeutic target for cervical cancer.     

Lack of definitive presurgical pathological diagnosis is associated with inadequate surgical margins in breast-conserving surgery

PurposeTo determine the impact of definitive presurgical diagnosis on surgical margins in breast-conserving surgery (BCS) for primary carcinomas; clinicopathological features were also analyzed.MethodsThis retrospective study included women who underwent BCS for primary carcinomas in 2016 and 2017. Definitive presurgical diagnosis was defined as having a presurgical core needle biopsy (CNB) and not being upstaged between biopsy and surgery. Biopsy data and imaging findings including breast density were retrieved. Inadequate surgical margins (IM) were defined per latest ASCO and ASTRO guidelines. Univariable and multivariable analyses were performed.Results360 women (median age, 66) met inclusion criteria with 1 having 2 cancers. 82.5% (298/361) were invasive cancers while 17.5% (63/361) were ductal carcinoma in situ (DCIS). Most biopsies were US-guided (284/346, 82.0%), followed by mammographic (60/346, 17.3%), and MRI-guided (2/346, 0.6%). US and mammographic CNB yielded median samples of 2 and 4, respectively, with a 14G needle. 15 patients (4.2%) lacked presurgical CNB. The IM rate was 30.0%. In multivariable analysis, large invasive cancers (>20 mm), dense breasts, and DCIS were associated with IM (p = 0.029, p = 0.010, and p = 0.013, respectively). Most importantly, lack of definitive presurgical diagnosis was a risk factor for IM (OR, 2.35; 95% CI: 1.23–4.51, p = 0.010). In contrast, neither patient age (<50) nor aggressive features (e.g., LVI) were associated with IM.ConclusionLack of a definitive presurgical diagnosis was associated with a two-fold increase of IM in BCS; other risk factors were dense breasts, large invasive cancers, and DCIS.     

Can patients with head and neck cancers invading carotid artery gain survival benefit from surgery?

Conclusion. Surgical treatment of carotid invasion may give an improved 2-year survival in selected patients without significant morbidity. Objective. To evaluate survival outcomes in patients with head and neck squamous cell carcinomas invading the carotid artery. Patients and methods. At the time of carotid invasion, 23 patients underwent surgery (n=11), chemoradiotherapy (n=6), or palliation (n=6). Surgical methods included carotid resection and ligation (n=5), carotid resection and reconstruction with saphenous vein (n=4), and peeling (n=2). Survival outcomes among different treatments were compared. Results. None of the 11 surgical patients experienced perioperative mortality or major neurologic complications. Three of these patients survived, but two had recurrent disease at last follow-up; their 2-year overall survival and disease-free survival rates were 24.5% and 18.2%, respectively. In contrast, all patients treated with chemoradiation or palliation died within 15 months. Median survival time was 16.5 months in the surgery group, 11.5 months in the chemoradiation group, and 3 months in the palliation group (p=0.025).     

下调ENAH 对肝癌细胞侵袭和迁移能力的影响

目的:探讨ENAH对肝癌细胞侵袭和迁移能力的影响及其机制。方法:用实时定量聚合酶链反应(RT-PCR)的方法在mRNA水平测定ENAH在48对结肠癌组织及正常组织中的表达；改变ENAH表达后检测肝癌细胞系中ENAH，Transwell实验检测其侵袭和迁移能力。结果:RT-PCR结果显示:ENAH在肝癌组织中的表达高于正常组织；相比正常肝细胞系，ENAH在Huh7及BEL7402中的表达升高。下调ENAH在Huh7及BEL7402中的表达后，Transwell实验结果显示肝癌细胞系Huh7及BEL7402的运动、侵袭和迁移能力均明显减弱。结论:ENAH能够促进肝癌细胞系Huh7和BEL7402的侵袭和迁移能力。     

MiR-200c-3p inhibits cell migration and invasion of clear cell renal cell carcinoma via regulating SLC6A1

In this study, we investigated the mechanism of miR-200c-3p and SLC6A1 in regulating cell activity of clear cell renal cell carcinoma (CCRCC). The mRNA and miRNA expressions of tissue specimens were analyzed by CapitalBio Corporation (Beijing, China). The expression of SLC6A1 in CCRCC cells was examined through qRT-PCR and western blot. The migration and invasion ability of 786-O cells was testified by transwell assay after transfected. 786-O cell proliferation ability was detected by MTT assay. Dual luciferase reporter assay verified the association between SLC6A1 and miR-200c-3p. SLC6A1 was high expressed and miR-200c-3p was low expressed in CCRCC tissues and cells. Besides, lower SLC6A1 expression indicated longer survival time and higher survival rate. MiR-200c-3p could directly target at SLC6A1 and reduce its expression. MiR-200c-3p inhibited the proliferation, migration and invasion in 786-O cells by down-regulating SLC6A1 expression. The results suggested that the miR-200c-3p served as a suppressor for CCRCC via down-regulating SLC6A1.