组织蛋白酶B与肿瘤

组织蛋白酶B(CB)能够直接降解或激活纤溶酶原激活剂及基质金属蛋白酶等而间接降解许多细胞外基质成分,从而参与肿瘤的侵袭转移过程.此外它还可以促进肿瘤血管的增生,增强肿瘤细胞的运动能力,而且CB转录、表达水平的高低与肿瘤的预后呈正相关.现综述CB的基因调控、蛋白结构特点、生物学特性及在肿瘤中的作用和意义.     

Chemotherapy and the tumor microenvironment: the contribution of circulating endothelial cells

Anti-angiogenic drugs, alone or in combination with chemotherapeutics, are increasingly used by medical oncologists. In many cases, however, their mechanism of action and the tailoring of optimal dosage/schedule are still elusive. Circulating endothelial cell (CEC) and progenitor (CEP) number and viability are modulated in a large series of diseases including cancer, and look promising as surrogate biomarkers for the definition of the optimal biological dose of anti-angiogenic drugs and for patients’ stratification. Along with CECs and CEPs, potential EC- and CEP-related surrogate molecular markers such as VE-Cadherin and CD133 are currently under preclinical and clinical investigation.     

Diabetes mellitus contribution to the remodeling of the tumor microenvironment in gastric cancer

Compelling pieces of evidence derived from both clinical and experimental research has demonstrated the crucial contribution of diabetes mellitus (DM) as a risk factor associated with increased cancer incidence and mortality in many human neoplasms, including gastric cancer (GC). DM is considered a systemic inflammatory disease and therefore, this inflammatory status may have profound effects on the tumor microenvironment (TME), particularly by driving many molecular mechanisms to generate a more aggressive TME. DM is an active driver in the modification of the behavior of many cell components of the TME as well as altering the mechanical properties of the extracellular matrix (ECM), leading to an increased ECM stiffening. Additionally, DM can alter many cellular signaling mechanisms and thus favoring tumor growth, invasion, and metastatic potential, as well as key elements in regulating cellular functions and cross-talks, such as the microRNAs network, the production, and cargo of exosomes, the metabolism of cell stroma and resistance to hypoxia. In the present review, we intend to highlight the mechanistic contributions of DM to the remodeling of TME in GC.     

粘液性大肠癌组织蛋白酶B、D表达与肿瘤浸润

目的组织蛋白酶B(Cathepsin B,CB)在粘液性大肠癌的表达尚未明了.组织蛋白酶D(Cathepsin D,CD)在肿瘤浸润和转移中的作用仍存在争议.本实验目的系探讨粘液性大肠癌CB和CD表达及其与肿瘤浸润转移的关系.方法采用免疫组化方法对48例人不同类型大肠癌CB及CD表达进行半定量检测.结果伴淋巴结转移大肠癌CB和CD表达率高于不伴淋巴结转移大肠癌,差异具显著性(P＜0.05;P＜0.005).粘液性大肠癌CB表达高于非粘液性者,差别具显著性(P＜0.05),但CD表达差异却无显著性意义(P＞0.05).结论提示大肠癌CB和CD表达与肿瘤浸润转移有关,CB在粘液性大肠癌浸润转移中作用可能更为重要.     

Immune regulation within human tumors - contribution of different components of the tumor microenvironment

We have examined the ability of various components of breast, colorectal and ovarian tumours to regulate the activation and function of LAK cells and TILs, immune effectors which have been used as anti-tumour therapies. Tumour cell or supernatants derived from their short-term in vitro culture, inhibited the activation of PBMC by IL-2 but supported the continued proliferation of LAK or TIL cells which had already been activated. Despite being able to enhance or suppress growth of a range of cell lines, a cell-free, soluble preparation (TDS) from primary tumours was uniformly inhibitory to IL-2 activated cells, suggesting that it reflected the immunoregulatory nature of human tumours more accurately than cell-cultures or their supernatants.     

Melanoma and the tumor microenvironment

Melanoma arises through the accrual of mutations in genes critical for proliferation and survival. Although melanoma had been traditionally conceptualized as a cell-autonomous event, increasing evidence supports the notion that these tumors are not isolated entities but rather depend, interact with, and react to the adjacent microenvironment. Melanoma is composed of not only the malignant cells but also the supporting stroma, which includes fibroblasts, endothelial cells, immune cells, soluble molecules, and the extracellular matrix (ECM). Tumor cells actively interact with the microenvironment in a bidirectional manner through molecular signals that modulate the malignant phenotype. This article briefly reviews the molecular basis of melanomagenesis as well as the interplay of melanoma with other cells of the tumor microenvironment and components of the ECM. It also discusses the influence of the microenvironment on therapeutic targeting of melanoma, highlighting recent studies that propose novel strategies to target tumor-microenvironment interactions.     

组织蛋白酶S与恶性肿瘤

组织蛋白酶s（Cathepsin S,Cat  S）是一种半胱氨酸蛋白酶,属于木瓜蛋白酶家族成员之一,不仅在多种生物体中表达,而且参与包括肿瘤在内的多种疾病的发生过程。近年研究发现,Cat  S与肝癌、肺癌、乳腺癌和结直肠癌等多种肿瘤的发生发展、侵袭转移以及预后等密切相关,推测其有望成为多种肿瘤临床诊治的新靶点。本文就Cat  S与这些肿瘤的发生发展关系、调控分子机制、诊断和治疗等相关研究进展作一综述。     

A novel signaling role for miR-451 in esophageal tumor microenvironment and its contribution to tumor progression

Objective

We evaluated miR-451 expression in serum and tissue samples of esophageal squamous cell carcinoma (ESCC) patients. Then, we examined a secretory role of miR-451 in esophageal tumor microenvironment.

Methods

miR-451 expression was evaluated in 39 serum samples from esophageal SCC patients compared to 39 normal individuals as well as 26 pairs of fresh-frozen tumor and adjacent normal tissues from patients with ESCC, using qRT-PCR. In a co-culture system of human normal fibroblasts (HFSF-PI3) and esophageal cancer cell line (KYSE-30), we evaluated exosomal miR-451 secretion into the conditioned medium (CM) of both cell lines. Then, we analyzed the effect of primiR-451-transfected fibroblasts on the migration potency of their neighboring KYSE-30 cells.

Results

We detected miR-451 over-expression in serum samples of esophageal cancer patients compared to the normal group (P = 0.005). Interestingly, fresh-frozen tumor tissues from the same patients showed miR-451 down-regulation compared to their adjacent normal counterparts (P = 0.043). Co-culturing the KYSE-30 cell line with normal fibroblasts significantly induced miR-451 exosomal secretion into the CM. Moreover, co-culture of KYSE-30 cell line with miR-451-over-expressing fibroblasts significantly induced migration tendency in KYSE-30 cell line compared to the mock-transfected fibroblasts (P < 0.0001). In this system, MIF expression (a validated target of miR-451) in the KYSE-30 cell line was increased although this alteration was not statistically significant (fold change = 4.44).

Conclusions

Our data suggest that cancer-associated fibroblasts use exosomal miR-451 as a signaling molecule to provide a favorable niche for tumor cell migration and cancer progression. Our findings provide new insights into the stromal role of miR-451 in the esophageal tumor microenvironment as a communicatory molecule and suggest a signaling role for miR-451 in extracellular matrix cross-talks.

     

Hepatitis B virus X protein in liver tumor microenvironment

Encoded by the hepatitis B virus, hepatitis B virus X protein (HBx) is a multifunctional, potentially oncogenic protein that acts primarily during the progression from chronic hepatitis B to cirrhosis and hepatocellular carcinoma (HCC). In recent decades, it has been established that chronic inflammation generates a tumor-supporting microenvironment. HCC is a typical chronic inflammation-related cancer, and inflammation is the main risk factor for HCC progression. The viral transactivator HBx plays a pivotal role in the initiation and maintenance of hepatic inflammatory processes through interactions with components of the tumor microenvironment including tumor cells and the surrounding peritumoral stroma. The complex interactions between HBx and this microenvironment are thought to regulate tumor growth, progression, invasion, metastasis, and angiogenesis. In this review, we have summarized the current evidence evaluating the function of HBx and its contribution to the inflammatory liver tumor microenvironment.     

肿瘤微环境与肿瘤

适宜的微环境可以引起基因组不稳定、提供支架和屏障、产生免疫豁免区域、诱导双向分化和形成许可微环境,促进肿瘤的发生.在肿瘤发展的过程中,肿瘤又形成组织缺氧、pH值降低、营养缺乏和肿瘤血管生成等特点的肿瘤微环境.肿瘤微环境既是肿瘤发生的原因又是肿瘤发展的结果.理解肿瘤微环境在肿瘤发生发展中的作用可能为肿瘤治疗提供新的策略.     

Evolution of tumor invasiveness: the adaptive tumor microenvironment landscape model

Interactions between cancer cells and their microenvironment are crucial for promoting tumor growth and invasiveness. In the tumor adaptive landscape model, hypoxic and acidic microenvironmental conditions reduce the fitness of cancer cells and significantly restrict their proliferation. This selects for enhanced motility as cancer cells may evolve an invasive phenotype if the consequent cell movement is rewarded by proliferation. Here, we used an integrative approach combining a mathematical tumor adaptive landscape model with experimental studies to examine the evolutionary dynamics that promote an invasive cancer phenotype. Computer simulation results hypothesized an explicit coupling of motility and proliferation in cancer cells. The mathematical modeling results were also experimentally examined by selecting Panc-1 cells with enhanced motility on a fibroblast-derived 3-dimensional matrix for cells that move away from the unfavorable metabolic constraints. After multiple rounds of selection, the cells that adapted through increased motility were characterized for their phenotypic properties compared with stationary cells. Microarray and gene depletion studies showed the role of Rho-GDI2 in regulating both cell movement and proliferation. Together, this work illustrates the partnership between evolutionary mathematical modeling and experimental validation as a potentially useful approach to study the complex dynamics of the tumor microenvironment.     

Inhibition of tumor lactate oxidation: Consequences for the tumor microenvironment

Background and purpose

Tumor cells are recognized as being highly glycolytic. However, recently it was suggested that lactate produced in hypoxic tumor areas may be taken up by the monocarboxylate transporter MCT1 and oxidized in well-oxygenated tumor parts. Furthermore, it was shown that inhibition of lactate oxidation using the MCT1 inhibitor α-cyano-hydroxycinnamate (CHC) can radio-sensitize tumors possibly by forcing a switch from lactate oxidization to glycolysis in oxygenated cells, which in turn improves tumor oxygenation and indirectly kills radio-resistant hypoxic tumor cells from glucose starvation.

Material and methods

To provide direct evidence for the existence of a targetable energetic symbiosis, mice bearing SiHa or FaDu_dd tumors were treated with CHC for different time periods. One hour prior to sacrifice, mice were administered with the glucose analog fluorodeoxyglucose (FDG) and the hypoxia-marker pimonidazole. Tumor cryosections were analyzed for regional glucose retention (FDG autoradiograms), hypoxia (pimonidazole retention) and glucose and lactate levels (bioluminescence imaging).

Results

Treatment did not influence metabolite concentrations, necrosis or extent of hypoxia, but pixel-by-pixel analysis comparing FDG retention and hypoxia (a measure of the apparent in vivo Pasteur effect) showed that CHC treatment caused a transient reduction in the Pasteur effect in FaDu_dd 1.5 h following CHC administration whereas a reduction was only observed in SiHa following repeated treatments.

Conclusions

In summary, our data show that CHC is able to influence the intratumoral distribution of glucose use between hypoxic and non-hypoxic tumor areas. That is in accordance with a functional tumor lactate-shuttle, but the absence of any detectable changes in hypoxic extent and tissue metabolites was unexpected and warrants further investigation.     

Metastasis suppressors and the tumor microenvironment

The most lethal and debilitating attribute of cancer cells is their ability to metastasize. Throughout the process of metastasis, tumor cells interact with other tumor cells, host cells and a variety of molecules. Tumor cells are also faced with a number of insults, such as hemodynamic sheer pressure and immune selection. This brief review explores how metastasis suppressor proteins regulate interactions between tumor cells and the microenvironments in which tumor cells find themselves.     

协同刺激分子B7-H4与肿瘤微环境的研究进展

协同刺激分子B7-H4是B7家族新成员,具有负性T淋巴细胞免疫调节作用。B7-H4在肿瘤微环境中的表达、调控和功能对肿瘤免疫逃逸起到重要的作用。研究B7-H4在肿瘤微环境的表达及意义,不仅有助于阐明肿瘤免疫逃逸机制,更为肿瘤免疫治疗提供新的靶点和策略。     

Myeloid-derived suppressor cells: Roles in the tumor microenvironment and tumor radiotherapy

Cancer progression is closely related to the tumor microenvironment in which the tumor exists, including surrounding blood vessels, immune cells, fibroblasts, bone marrow-derived inflammatory cells, signaling molecules and the extracellular matrix. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can impact the growth and evolution of cancerous cells. One of major cell components in the tumor microenvironment is myeloid-derived suppressor cells (MDSCs), which promote tumor growth and metastasis directly or indirectly by recognizing other immune cells, producing cytokines and exerting their immunosuppression functions. MDSCs have emerged as major regulators of immune responses in cancer and key targets for treating cancer. There are many limitations and side-effect in approaches of conventional cancer therapy, including radiotherapy. It has grown up to be a burgeoning field that a combination of radiotherapy and immunotherapy applied to cancer therapy. Therefore, it is fundamental to explore the immune mechanism in the process of cancer treatment. Here, we reviewed the recent progress of MDSCs in roles of the tumor microenvironment and tumor radiotherapy.