Stromal transforming growth factor-beta 1 is crucial for reinforcing the invasive potential of low invasive cancer

Objective

Tumour cells alter the characteristics of the adjacent stroma to create a supportive microenvironment during cancer progression. In vitro and in vivo experiments were carried out to verify the role of stromal TGF-β1 in reinforcing of the invasive potential in low invasive cancer.

Materials and methods

Isolated NF or CAF was co-cultured with low invasive HSC-2 cells to evaluate whether stromal TGF-β1 induced PDPN expression by Transwell invasion and influenced tumour growth in orthotopic xenografts.

Results

Stimulation by TGF-β1 promoted PDPN expression and Transwell invasion through SMAD signalling as well as activation of Src, P38 mitogen activated protein kinase and extracellular regulated kinase 1/2. PDPN induction was TβRII-dependent. Tumour growth of HSC-2 OSCC in a mouse xenograft was intensified in the tumour CAF microenvironment.

Conclusions

Stromal TGF-β1 signalling promoted PDPN expression in cancer cells, thereby enhancing tumour growth and leading to a more invasive phenotype.     

Clinicopathology significance of podoplanin immunoreactivity in esophageal squamous cell carcinoma

Backgroud and aim: Podoplanin (D2-40) is a specific marker for lymphatic endothelium. The vast majority of previous studies on podoplanin immunostaining in esophageal squamous cell carcinoma (ESCC) focused on identifying lymphatic vessel invasion (LVI) and counting lymphatic vessel density (LVD) and had contradictory results. Recent studies show podoplanin expression on cancer cells or tumor stroma in several cancers, which have specific significance; but the status in ESCC remains unclear. Therefore, the aim of this study was to further study and summarize the clinicopathological significance of podoplanin immunoreactivity in ESCC. Materials and methods: We examined podoplanin expression in tissue specimens from 107 patients with ESCC by immunohistochemistry. Podoplanin positive lymphatic vessels in intratumoral and peritumoral tissues and podoplanin positive expression in cancer cells and tumor stroma were analyzed, and correlated with clinicopathologic parameters and three-year overall and free-disease survival. Results: 34 (31.8%) and 28 (26.2%) of 107 specimens had podoplanin positive expression in cancer cells and tumor stroma, respectively. Logistic regression analysis showed high intratumoral lymphatic vessel density (I-LVD) and podoplanin positivity in cancer cells were increased risks of lymph node metastasis (LNM) (OR = 2.45, P = 0.03; OR = 0.35, P = 0.01, respectively). Survival analysis showed that I-LVD was a significant factor related to poor three-year overall and free-disease survival (P = 0.04, P = 0.03, respectively). Conclusions: Previous data and our results show that podoplanin seems to be a useful marker to predict LNM, recurrence, and worse prognosis in ESCC; in particular, LVI, high I-LVD, and podoplanin positivity in cancer cells are associated with LNM, recurrence and overall survival.     

Bmi-1、Podoplanin和p53在胸腺上皮肿瘤中的表达及意义

目的根据WHO胸腺上皮肿瘤(TET)最新分类标准,研究Bmi-1、Podoplanin和p53在TET中的表达及临床意义。方法采用组织芯片技术制作110例TET组织芯片,免疫组化NovoLinkTMPolymer法检测TET中Bmi-1、Podoplanin和p53的表达情况。结果在110例TET中,Bmi-1的阳性表达率为68.2%,Podoplanin的阳性表达率为41.8%,p53的阳性表达率为42.7%。Bmi-1、Podoplanin和p53的阳性表达率与TET的病理组织学分型、Masaoka分期及临床病理分级等有显著相关性(P<0.05),而且Bmi-1和p53的表达呈正相关(r=0.941,P=0.005)。结论Bmi-1、Podoplanin和p53在TET的发生发展中起着重要作用,对指导临床治疗和预后评估有着重要参考价值。     

Podoplanin和CD34在宫颈癌中的表达及其意义

目的:研究Podoplanin、CD34在宫颈癌中的表达及其意义。方法:用免疫组化方法检测53例早期宫颈癌ICC和15例癌旁正常宫颈上皮(NEC)中Podoplanin和CD34表达情况。结果:宫颈癌组织中Podoplanin和CD34阳性表达率分别为90.5%、100%。Podoplanin在宫颈癌旁正常宫颈组织未发现阳性表达。宫颈癌组织Podoplanin和CD34表达呈正相关。(χ2=23.432,P<0.05),二者的联合表达与淋巴结转移及预后密切相关(P<0.05)。结论:Podoplanin和CD34可能在宫颈癌的发生发展过程中起关键作用,二者在肿瘤转移过程中密切相关。检测其表达水平,对于宫颈癌的诊断、恶性程度及预后的判断有一定价值。     

血管内皮生长因子C和Podoplanin对老年直肠癌淋巴结转移预后评价的价值

目的 探讨血管内皮生长因子C（VEGF-C）、Podoplanin在老年直肠癌淋巴结转移组织中的表达及其与预后的关系。方法 免疫组织化学法研究VEGF-C、Podoplanin在老年直肠癌及其相应淋巴结转移癌组织中的表达,同时了解术后随访情况。结果 老年直肠癌淋巴结转移组织中VEGF-C、Podoplanin的表达率均高于其相应的原发癌组织。有淋巴结转移的老年直肠癌组织VEGF-C、Podoplanin的表达显著高于无淋巴结转移的癌组织,差异有统计学意义（P<0.05）。VEGF-C、Podoplanin的表达水平和淋巴结转移是影响老年直肠癌患者预后的重要因素。结论 VEGF-C及Podoplanin在老年直肠癌淋巴结转移组织中的高表达,与直肠癌的预后有关。两者联合可以作为判断老年直肠癌淋巴结转移患者预后的检测指标。     

Increased density and diameter of lymphatic microvessels correlate with lymph node metastasis in early stage invasive colorectal carcinoma

To determine whether lymphangiogenesis was associated with the development of colorectal carcinoma and whether the mean maximal diameter of lymphatic microvessels (LMMMD) or lymphatic microvessel density (LMVD) is associated with lymph node metastasis in early stage invasive colorectal carcinoma (T1 carcinoma), we used immunohistochemical staining with podoplanin to measure LMMMD and LMVD in intratumoral (LMMMDit, LMVDit) and peritumoral areas (LMMMDpt, LMVDpt) of T1 carcinomas (n=87). By comparing the LMMMD and LMVD in normal large intestine (n=10), adenoma (n=15), and Tis carcinoma (n=15), we found out that the LMVDpt in T1 carcinoma with lymphatic vessel invasion (LVI) was significantly high (P<0.001), and there was a significant decrease in LMMMDpt in T1 carcinoma (P=0.031). Both LMMMDpt and LMVDpt were significantly increased in the T1 carcinomas, with LVI compared with the T1 carcinomas without LVI (P=0.018, P=0.003). Multivariate analysis revealed that LVI and combined greater LMMMDpt and greater LMVDpt were associated with lymph node metastases (P=0.005, P=0.036). These results indicate that lymphangiogenesis might be induced in the surrounding tumor areas of the T1 colorectal carcinoma with LVI; thus, evaluation of the diameter and density of lymphatic microvessels is important in T1 colorectal carcinoma to predict lymph node metastases.     

胃癌癌周微淋巴管与淋巴道转移的关系及其意义

目的 探讨胃癌癌周微淋巴管与淋巴道转移的关系及其与临床病理特征之间的关系.方法 采用微淋巴管特异标记物Podoplanin标记微淋巴管,用Ki-67检测微淋巴管内皮细胞的增殖活性,在一张切片上同时测定56例胃癌组织微淋巴管密度及其增殖活性,并结合胃癌临床病理特征进行分析.结果 胃癌癌周微淋巴管密度与肿瘤的分化程度、淋巴结转移以及淋巴管受累有关(F=14.96,t=4.51、4.11;P<0.05、0.01).胃癌癌周微淋巴管内皮细胞Ki-67指数仅与淋巴管受累有关系(t=3.73,P<0.01).结论 胃癌癌周微淋巴管可能促进肿瘤淋巴道转移;胃癌癌周微淋巴管密度是评价其分化程度、淋巴结转移及淋巴管受累的有价值的指标.     

The brain-tumor related protein podoplanin regulates synaptic plasticity and hippocampus-dependent learning and memory

Introduction: Podoplanin is a cell-surface glycoprotein constitutively expressed in the brain and implicated in human brain tumorigenesis. The intrinsic function of podoplanin in brain neurons remains however uncharacterized.

Materials and methods: Using an established podoplanin-knockout mouse model and electrophysiological, biochemical, and behavioral approaches, we investigated the brain neuronal role of podoplanin.

Results: Ex-vivo electrophysiology showed that podoplanin deletion impairs dentate gyrus synaptic strengthening. In vivo, podoplanin deletion selectively impaired hippocampus-dependent spatial learning and memory without affecting amygdala-dependent cued fear conditioning. In vitro, neuronal overexpression of podoplanin promoted synaptic activity and neuritic outgrowth whereas podoplanin-deficient neurons exhibited stunted outgrowth and lower levels of p-Ezrin, TrkA, and CREB in response to nerve growth factor (NGF). Surface Plasmon Resonance data further indicated a physical interaction between podoplanin and NGF.

Discussion: This work proposes podoplanin as a novel component of the neuronal machinery underlying neuritogenesis, synaptic plasticity, and hippocampus-dependent memory functions. The existence of a relevant cross-talk between podoplanin and the NGF/TrkA signaling pathway is also for the first time proposed here, thus providing a novel molecular complex as a target for future multidisciplinary studies of the brain function in the physiology and the pathology.

• Key messages

• Podoplanin, a protein linked to the promotion of human brain tumors, is required in vivo for proper hippocampus-dependent learning and memory functions.

• Deletion of podoplanin selectively impairs activity-dependent synaptic strengthening at the neurogenic dentate-gyrus and hampers neuritogenesis and phospho Ezrin, TrkA and CREB protein levels upon NGF stimulation.

• Surface plasmon resonance data indicates a physical interaction between podoplanin and NGF. On these grounds, a relevant cross-talk between podoplanin and NGF as well as a role for podoplanin in plasticity-related brain neuronal functions is here proposed.