Targeting the tumour microenvironment in ovarian cancer

The study of cancer initiation, growth, and metastasis has traditionally been focused on cancer cells, and the view that they proliferate due to uncontrolled growth signalling owing to genetic derangements. However, uncontrolled growth in tumours cannot be explained solely by aberrations in cancer cells themselves. To fully understand the biological behaviour of tumours, it is essential to understand the microenvironment in which cancer cells exist, and how they manipulate the surrounding stroma to promote the malignant phenotype.Ovarian cancer is the leading cause of death from gynaecologic cancer worldwide. The majority of patients will have objective responses to standard tumour debulking surgery and platinum-taxane doublet chemotherapy, but most will experience disease recurrence and chemotherapy resistance. As such, a great deal of effort has been put forth to develop therapies that target the tumour microenvironment in ovarian cancer. Herein, we review the key components of the tumour microenvironment as they pertain to this disease, outline targeting opportunities and supporting evidence thus far, and discuss resistance to therapy.     

Factors controlling the pharmacokinetics,biodistribution and intratumoral penetration of nanoparticles

Nanoparticle drug delivery to the tumor is impacted by multiple factors: nanoparticles must evade clearance by renal filtration and the reticuloendothelial system, extravasate through the enlarged endothelial gaps in tumors, penetrate through dense stroma in the tumor microenvironment to reach the tumor cells, remain in the tumor tissue for a prolonged period of time, and finally release the active agent to induce pharmacological effect. The physicochemical properties of nanoparticles such as size, shape, surface charge, surface chemistry (PEGylation, ligand conjugation) and composition affect the pharmacokinetics, biodistribution, intratumoral penetration and tumor bioavailability. On the other hand, tumor biology (blood flow, perfusion, permeability, interstitial fluid pressure and stroma content) and patient characteristics (age, gender, tumor type, tumor location, body composition and prior treatments) also have impact on drug delivery by nanoparticles. It is now believed that both nanoparticles and the tumor microenvironment have to be optimized or adjusted for optimal delivery. This review provides a comprehensive summary of how these nanoparticle and biological factors impact nanoparticle delivery to tumors, with discussion on how the tumor microenvironment can be adjusted and how patients can be stratified by imaging methods to receive the maximal benefit of nanomedicine. Perspectives and future directions are also provided.     

彩色多普勒用于足月新生儿缺氧缺血性脑病颅内静脉系统检查

目的 观察缺氧缺血新生儿的颅内静脉系统的血流特点,为临床判定缺氧缺血性脑病提供新的参考依据.方法 实验组缺氧缺血新生儿52例,对照组正常足月新生儿52例,通过前囟门应用彩色多普勒观察颅内静脉系统中直窦(SS)、上矢状窦(sss)、双侧横窦(Ts)、双侧室管膜下静脉(SV)及双侧大脑内静脉(ICV)的最大平均血流速度及频谱形态.结果 与对照组相比较,实验组SSS、双侧ICV及双侧SV平均最大血流速度减低.对照组SSS频谱为搏动型,双侧ICV及双侧SV频谱为连续平坦型.实验组SSS的频谱形态可见连续平坦型,SS及双侧TS的频谱形态存在搏动型及连续平坦型.颅内双侧ICV及双侧SV的频谱为连续乎坦型.结论 颅内静脉系统中,SSS、双侧ICV及双侧SV为提示缺氧缺血性脑病的合适观察对象.     

Tumour‐associated mast cells in classical Hodgkin's lymphoma: correlation with histological subtype,other tumour‐infiltrating inflammatory cell subsets and outcome

The tumour microenvironment in classical Hodgkin's lymphoma (cHL) is characterised by a minor population of neoplastic Hodgkin and Reed–Sternberg cells within a heterogeneous background of non‐neoplastic bystanders cells, including mast cells. The number of infiltrating mast cells in cHL has been reported to correlate with poor prognosis. We used immunohistochemistry to assess the degree of tumour‐infiltrating mast cells in cHL tissue microarrays and correlated this with clinico‐pathological features and prognosis in a cohort of homogeneously treated patients with Hodgkin's disease. A high degree of tumour mast cells was associated with nodular sclerosis (NS) subtype histology (P = 0.0002). Moreover, the number of mast cells was inversely correlated with the numbers of CD68+ and CD163+ macrophages (P = 0.0001 and P = 0.003, respectively) and with the number of granzyme+ cytotoxic cells (P = 0.004). The degree of mast cell infiltration was not a prognostic factor in cHL of nodular sclerosis subtype. In contrast, in mixed cellularity cHL a high number of intratumoral mast cells correlated with significantly poorer outcome both in terms of overall (P = 0.03) and event‐free survival (P = 0.01). Further studies are warranted into the biological mechanisms underlying this adverse outcome and their possible therapeutic implications.     

Systemic inflammation promotes lung metastasis via E-selectin upregulation in mouse breast cancer model

Systemic inflammation might modulate the microenvironment in the lungs and promotes metastasis. E-selectin, an inflammation inducible endothelial cell adhesion molecule, has been reported to play an important role in homing metastatic cancer cells. To study the effects of E-selectin expression induced by systemic inflammation on breast cancer metastasis, we first treated BALB/c mice with lipopolysaccharide (LPS) to induce systemic inflammation. Pulmonary tissues were analyzed by wet/dry ratio, hematoxylin and eosin (H&E) staining and immunohistochemistry. Then 4T1 cells were injected via tail vein. Lung surface metastasis was counted and detected by histological analysis. LPS-induced E-selectin expression and tumor cells adhesion were assessed by western blotting and immunofluorescence. The circulating levels of proinflammatory cytokines in sera were evaluated by ELISA. Our results showed that a significant increase in breast cancer metastasis to lungs was observed in LPS-treated mice vs. the PBS-treated mice, accompanying with an increased E-selectin expression in pulmonary tissue of LPS-treated mice. In vitro studies showed a significant elevation of E-selectin production in MPVECs which enhanced the adhesion activity of 4T1 cells. Treatment with anti-E-selectin antibody significantly reduced the development of metastasis in vivo, and significantly reduced the adhesion of 4T1 cells to MPVECs in vitro. Our results suggest that systemic inflammation may increase the expression of E-selectin which mediated the lung metastasis of breast cancer in mouse model.     

Long-Term Follow-Up of R-CHOP With Bevacizumab as Initial Therapy for Mantle Cell Lymphoma: Clinical and Correlative Results

BackgroundEmerging evidence indicates that MCL has increased angiogenesis within the tumor microenvironment. We initiated a phase II trial to determine if the addition of bevacizumab to the standard R-CHOP regimen could enhance antitumor effects in patients with previously untreated MCL.Patients and MethodsEleven patients with previously untreated MCL received bevacizumab at 15 mg/kg on day 1, and standard CHOP-21 (CHOP given every 21 days per cycle) with rituximab (375 mg/m² per cycle) on day 3 of each cycle for a total of 6 cycles. Planned study end points included safety and efficacy assessment, and exploratory analysis of angiogenic profiles. The study was suspended in August of 2010 based on safety findings in DLBCL (diffuse large B-cell lymphoma) of increased cardiovascular events with the regimen.ResultsBeyond the standard R-CHOP safety profile, Grade 3 left ventricular dysfunction developed in 2 patients (18%), Grade 1/2 hypertension, proteinuria, and bleeding each developed in 1 patient (9%). The overall response rate was 82% with 36% complete response (CR)/complete response unconfirmed (CRu). The median progression-free survival (n = 11) was 18 months (95% confidence interval, 3-not reached), and 3-year overall survival rate was 82%. Correlative studies showed increased vascular endothelial growth factor receptor 1 expression in tumor cells at baseline, and elevated levels of plasma vascular endothelial growth factor (VEGF) throughout treatment.ConclusionThe addition of bevacizumab to the standard R-CHOP regimen did not appear to significantly improve efficacy beyond that observed from previous studies using R-CHOP alone. Therapeutic strategies that provide sustained inhibition on VEGF-related and VEGF-independent targets within the tumor microenvironment might further improve antiangiogenic effects and warrant further exploration in MCL.     

新生儿缺血缺氧性脑病相关危险因素的分析

目的：探讨新生儿缺血缺氧性脑病（ HIE）发生的相关危险因素。方法回顾性分析绍兴市上虞妇幼保健院2008年1月至2013年1月收治的350例HIE患儿临床资料，另选取同期顺产的200例非HIE高危新生儿作为对照组，应用单因素分析和Logistic回归分析筛选HIE发生的相关危险因素。结果多因素Logistic回归显示分娩前因素只有妊娠期糖尿病与HIE相关（RR＝1．43，95％CI：1．08～2．12，P＜0．05），其他HIE独立预测因素均为分娩期因素，即羊水粪染、肩先露、脐带绕颈、产程延长、胎心监护异常、器械助产、急诊剖宫产、1min Apgar＜3分和5min Apgar＜5分（RR值分别为1．97、6．31、2．26、1．84、2．41、1．91、1．21、17．48和20．07，95％CI分别为1．38～3．67、3．44～12．42、1．52～5．20、1．09～4．65、1．14～5．96、1．24～4．77、1．04～2．39、8．21～174．26和7．26～164．28，均P＜0．05）。结论新生儿HIE与母体、胎儿等多种因素相关，其中分娩期是关键，其他因素通过影响分娩期因素起作用。     

RKIP regulates CCL5 expression to inhibit breast cancer invasion and metastasis by controlling macrophage infiltration

Accumulating evidence suggests that presence of macrophages in the tumor microenvironment add to the invasive and tumor-promoting hallmarks of cancer cells by secreting angiogenic and growth factors. RKIP is a known metastasis suppressor and interferes with several steps of metastasis. However, the mechanistic underpinnings of its function as a broad metastasis suppressor remain poorly understood. Here, we establish a novel pathway for RKIP regulation of metastasis inhibition through the negative regulation of RANTES/CCL5 thereby limiting tumor macrophage infiltration and inhibition of angiogenesis. Using a combination of loss- and gain-of-function approaches, we show that RKIP hinders breast cancer cell invasion by inhibiting expression of the CC chemokine CCL5 in vitro. We also show that the expression levels of RKIP and CCL5 are inversely correlated among clinical human breast cancer samples. Using a mouse allograft breast cancer transplantation model, we highlight that ectopic expression of RKIP significantly decreases tumor vasculature, macrophage infiltration and lung metastases. Mechanistically, we demonstrate that the inhibition of the CCL5 expression is the cause of the observed effects resulting from RKIP expression. Taken together, our results underscore the significance of RKIP as important negative regulator of tumor microenvironment.     

外泌体在胰腺癌中的研究现状与进展

外泌体是一种双层脂质膜连接囊泡样小体，存在于各种体液中，参与细胞及肿瘤微环境之间的物质运输和信号传递。外泌体含有多种生物活性分子，包括脂质、蛋白质、DNA、mRNA以及非编码RNA，可以通过这些活性分子影响肿瘤的发生和发展，甚至可以影响肿瘤的治疗。胰腺癌是一种常见的恶性肿瘤，侵袭性强，预后较差，死亡率高。胰腺癌来源的外泌体是胰腺肿瘤微环境中的重要组成部分，促使胰腺癌细胞成功逃避细胞凋亡的重要因素，并且可以促进肝脏转移微环境的形成。近年来，与胰腺癌相关的外泌体逐渐成为新的研究热点，研究发现外泌体有望成为早期胰腺癌筛查的新型生物学标志，并将为胰腺癌靶向治疗提供可行的技术基础。