非小细胞肺癌患者血清中miR-22检测的临床意义

目的探讨非小细胞肺癌(NSCLC)患者血清中miR-22的表达水平及其临床意义。方法采用实时荧光定量PCR法检测健康人对照和NSCLC患者血清中miR-22的表达量,并构建受试者操作特征(ROC)曲线计算miR-22的敏感性和特异性。结果 NSCLC患者化疗前血清中miR-22的表达水平显著高于正常人组(P0.05);miR-22在Ⅲ期+Ⅳ期中的表达水平显著高于Ⅰ期+Ⅱ期(P0.05);miR-22对Ⅲ期+Ⅳ期NSCLC检测的敏感性明显高于Ⅰ期+Ⅱ期(P0.01);miR-22在鳞癌和腺癌中的表达量无统计学差异(P0.05);与化疗前比较,晚期NSCLC患者miR-22的表达量明显降低(P0.05)。结论血清miR-22可能与NSCLC的形成和发展有关,NSCLC患者miR-22的检测对于NSCLC的辅助诊断和化疗疗效评价有一定的临床应用价值。     

Circ-SMARCA5 suppresses colorectal cancer progression via downregulating miR-39-3p and upregulating ARID4B

BackgroundCircular RNAs are crucial in tumorigenesis. However, little is known about their functions in colorectal cancer (CRC). Circ-SMARCA5 was found to be an oncogene or tumor suppresser in different types of cancers, but its exact role in CRC remains unknown. Here, we aim to identify the role of circ-SMARCA5 in CRC development.MethodsCirc-SMARCA5 expression was determined by qRT-PCR. CRC cell proliferation, migration, and invasion were detected by CCK-8, wound healing, and Transwell assays, respectively. Bioinformatics analysis was performed to predict target genes. The interaction of microRNA (miR) with circ-SMARCA5 or target genes was detected using luciferase reporter assay. Xenograft model was established to determine the effect of circ-SMARCA5 on CRC tumor growth in vivo.ResultsCirc-SMARCA5 expression was dramatically decreased in CRC cell lines and tissues. Circ-SMARCA5 overexpression inhibited CRC cell proliferation, migration and invasion. MiR-93–3p was predicted as a target of circ-SMARCA5 and its overexpression attenuated the anti-tumor effect of circ-SMARCA5 on CRC cells. Furthermore, we predicted AT-rich interaction domain 4B (ARID4B) as the target of miR-39–3p. Functional analysis showed that circ-SMARCA5 upregulated ARID4B expression via miR-39–3p. Additionally, in vivo studies demonstrated that circ-SMARCA5 suppressed CRC tumor progression.ConclusionCirc-SMARCA5 functions as a tumor suppressor by upregulating ARID4B expression via sponging miR-39–3p, and thereby inhibited CRC progression.     

Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression

Inflammation is widely recognized as an inducer of cancer progression. The inflammation-associated enzyme, inducible nitric oxide synthase (NOS2), has emerged as a candidate oncogene in estrogen receptor (ER)-negative breast cancer, and its increased expression is associated with disease aggressiveness and poor survival. Although these observations implicate NOS2 as an attractive therapeutic target, the mechanisms of both NOS2 induction in tumors and nitric oxide (NO)-driven cancer progression are not fully understood. To enhance our mechanistic understanding of NOS2 induction in tumors and its role in tumor biology, we used stimulants of NOS2 expression in ER⁻ and ER⁺ breast cancer cells and examined downstream NO-dependent effects. Herein, we show that up-regulation of NOS2 occurs in response to hypoxia, serum withdrawal, IFN-γ, and exogenous NO, consistent with a feed-forward regulation of NO production by the tumor microenvironment in breast cancer biology. Moreover, we found that key indicators of an aggressive cancer phenotype including increased S100 calcium binding protein A8, IL-6, IL-8, and tissue inhibitor matrix metalloproteinase-1 are up-regulated by these NOS2 stimulants, whereas inhibition of NOS2 in MDA-MB-231 breast cancer cells suppressed these markers. Moreover, NO altered cellular migration and chemoresistance of MDA-MB-231 cells to Taxol. Most notably, MDA-MB-231 tumor xenographs and cell metastases from the fat pad to the brain were significantly suppressed by NOS2 inhibition in nude mice. In summary, these results link elevated NOS2 to signals from the tumor microenvironment that arise with cancer progression and show that NO production regulates chemoresistance and metastasis of breast cancer cells.Inflammation is a major component of the tumor microenvironment and a driving force in cancer initiation, promotion, and progression (1–3). Epithelial cancers express markers of inflammation that promote disease progression and drug resistance through evasion of cell death pathways and increased tumor metastasis. Rapid cancer growth leads to tumor hypoxia and nutrient deprivation, which promotes chronic inflammatory feed-forward signaling and selection of resistant tumors that are clinically challenging and sometimes untreatable.Several proinflammatory proteins such as COX2, NF-κB, IL-6, IL-8, S100 calcium binding protein A8 (S100A8), and VEGF are markers of chronic inflammation in the tumor microenvironment. In addition, these proinflammatory mediators directly correlate with inducible nitric oxide synthase (NOS2), which is an emerging biomarker of aggressive tumors that predicts poor survival in patients with elevated tumor NOS2 expression (4–8). These and other clinical studies warrant an improved mechanistic understanding of intratumoral NOS2 regulation and endogenous NO production, which may be therapeutically beneficial.Toward this end, our laboratory and others have used NO donors to study NO signaling in cancer. However, intratumoral NOS2 induction by components of the tumor microenvironment, which produces endogenous NO at levels that promote disease progression and predict poor outcome, has not been examined. Herein, we have used cell culture conditions that simulate chronic inflammation in the tumor microenvironment, which include nutrient deprivation by serum withdrawal (SW), hypoxia, inflammatory cytokines, and NO donors to examine physiologic mechanisms of NOS2 induction and downstream effects of NO target activation in both estrogen receptor positive and negative (ER⁺ and ER⁻) breast cancer cells. In addition, we show in vivo effects of NOS2 inhibition on tumor growth and metastases in mice. Using this approach, we provide evidence of NOS2 as a key driver of feed-forward signaling that promotes chronic inflammation and cancer progression.     

CCR1 knockdown suppresses human non-small cell lung cancer cell invasion

Purpose  CC chemokine receptor 1 (CCR1) plays a critical role in the recruitment of leukocytes to the site of inflammation. Tumor invasion and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. In this study, we aimed to assess the role of CCR1 in non-small cell lung cancer (NSCLC). Methods  CCR1 expression was determined by Western blotting in two human NSCLC clones (95C and 95D) with different metastatic potential. We silenced CCR1 expression through microRNA-mediated RNA interference, and examined the invasiveness and proliferation of CCR1-silenced NSCLC cell through Matrigel assay and MTT assay. Matrix metalloproteinases (MMPs) activity was determined by gelatin zymography. Results  We found that expression of CCR1 was correlated with the aggressive phenotype of the NSCLC cells. CCR1 knockdown significantly suppressed the invasiveness of NSCLC cells, but had only a minor effect on cell proliferation. Moreover, we demonstrated that CCR1 knockdown significantly reduced the expression level of matrix metalloproteinase-9. Conclusions  These findings suggest that CCR1 contributes to NSCLC cell migration by stimulating cell invasion, independent of cell proliferation. CCR1 might be a new target for NSCLC therapy. C.-L. Wang and B.-S. Sun contributed equally to this work.     

Down-regulation of 14-3-3zeta suppresses anchorage-independent growth of lung cancer cells through anoikis activation

The family of 14-3-3 proteins has emerged as critical regulators of diverse cellular responses under both physiological and pathological conditions. Here, we report an important role of 14-3-3zeta in tumorigenesis through a mechanism that involves anoikis resistance. 14-3-3zeta is up-regulated in a number of cancer types, including lung cancer. Through an RNAi approach using human lung adenocarcinoma-derived A549 cells as a model system, we have found that knockdown of a single zeta isoform of 14-3-3 is sufficient to restore the sensitivity of cancer cells to anoikis and impair their anchorage-independent growth. Enhanced anoikis appears to be mediated in part by up-regulated BH3-only proteins, Bad and Bim, coupled with decreased Mcl-1, resulting in the subsequent activation of Bax. This study suggests a model in which anchorage-independent growth of lung cancer cells requires the presence of 14-3-3zeta. This work not only reveals a critical role of 14-3-3zeta in anoikis suppression in lung cancer cells, but also identifies and validates 14-3-3zeta as a potential molecular target for anticancer therapeutic development.     

Tumor suppression by cell competition through regulation of the Hippo pathway

Homeostatic mechanisms can eliminate abnormal cells to prevent diseases such as cancer. However, the underlying mechanisms of this surveillance are poorly understood. Here we investigated how clones of cells mutant for the neoplastic tumor suppressor gene scribble (scrib) are eliminated from Drosophila imaginal discs. When all cells in imaginal discs are mutant for scrib, they hyperactivate the Hippo pathway effector Yorkie (Yki), which drives growth of the discs into large neoplastic masses. Strikingly, when discs also contain normal cells, the scrib(-) cells do not overproliferate and eventually undergo apoptosis through JNK-dependent mechanisms. However, induction of apoptosis does not explain how scrib(-) cells are prevented from overproliferating. We report that cell competition between scrib(-) and wild-type cells prevents hyperproliferation by suppressing Yki activity in scrib(-) cells. Suppressing Yki activation is critical for scrib(-) clone elimination by cell competition, and experimental elevation of Yki activity in scrib(-) cells is sufficient to fuel their neoplastic growth. Thus, cell competition acts as a tumor-suppressing mechanism by regulating the Hippo pathway in scrib(-) cells.     

Adenosine monophosphate-activated protein kinase suppresses vascular smooth muscle cell proliferation through the inhibition of cell cycle progression

Vascular smooth muscle cell (VSMC) proliferation is a critical event in the development and progression of vascular diseases, including atherosclerosis. We investigated whether the activation of adenosine monophosphate-activated protein kinase (AMPK) could suppress VSMC proliferation and inhibit cell cycle progression. Treatment of human aortic smooth muscle cells (HASMCs) or isolated rabbit aortas with the AMPK activator 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) induced phosphorylation of AMPK and acetyl Co-A carboxylase. AICAR significantly inhibited HASMC proliferation induced by both platelet-derived growth factor-BB (PDGF-BB) and fetal calf serum (FCS). Treatment with AICAR inhibited the phosphorylation of retinoblastoma gene product (Rb) induced by PDGF-BB or FCS, and increased the expression of cyclin-dependent kinase inhibitor p21(CIP) but not that of p27(KIP). Pharmacological inhibition of AMPK or overexpression of dominant negative-AMPK inhibited both the suppressive effect of AICAR on cell proliferation and the phosphorylation of Rb, suggesting that the effect of AICAR is mediated through the activation of AMPK. Cell cycle analysis in HASMCs showed that AICAR significantly increased cell population in G0/G1-phase and reduced that in S- and G2/M-phase, suggesting AICAR induced cell cycle arrest. AICAR increased both p53 protein and Ser-15 phosphorylated p53 in HASMCs, which were blocked by inhibition of AMPK. In isolated rabbit aortas, AICAR also increased Ser-15 phosphorylation and protein expression of p53 and inhibited Rb phosphorylation induced by FCS. These data suggest for the first time that AMPK suppresses VSMC proliferation via cell cycle regulation by p53 upregulation. Therefore, AMPK activation in VSMCs may be a therapoietic target for the prevention of vascular diseases.     

MicroRNA-224 promotes tumor progression in nonsmall cell lung cancer

Lung cancer is the leading cause of cancer-related deaths worldwide. Despite advancements and improvements in surgical and medical treatments, the survival rate of lung cancer patients remains frustratingly poor. Local control for early-stage nonsmall cell lung cancer (NSCLC) has dramatically improved over the last decades for both operable and inoperable patients. However, the molecular mechanisms of NSCLC invasion leading to regional and distant disease spread remain poorly understood. Here, we identify microRNA-224 (miR-224) to be significantly up-regulated in NSCLC tissues, particularly in resected NSCLC metastasis. Increased miR-224 expression promotes cell migration, invasion, and proliferation by directly targeting the tumor suppressors TNFα-induced protein 1 (TNFAIP1) and SMAD4. In concordance with in vitro studies, mouse xenograft studies validated that miR-224 functions as a potent oncogenic miRNA in NSCLC in vivo. Moreover, we found promoter hypomethylation and activated ERK signaling to be involved in the regulation of miR-224 expression in NSCLC. Up-regulated miR-224, thus, facilitates tumor progression by shifting the equilibrium of the partially antagonist functions of SMAD4 and TNFAIP1 toward enhanced invasion and growth in NSCLC. Our findings indicate that targeting miR-224 could be effective in the treatment of certain lung cancer patients.Lung cancer is the second most common cancer and the leading cause of cancer-related death worldwide. In 2013, there were an estimated 228,190 new cases of lung cancer and 159,480 deaths in the United States. Despite advancements and improvements in surgical and medical treatments, the 5-y survival rate of lung cancer patients remains frustratingly poor (1). Although local control for early-stage nonsmall cell lung cancer (NSCLC) has dramatically improved over the last decades for both operable and inoperable patients (2, 3), ∼20% of early-stage patients, however, are developing distant metastasis (4, 5), and 10–15% of patients undergoing stereotactic ablative body radiation fail regionally (6). The molecular mechanisms of NSCLC invasion leading to regional and distant disease spread remain poorly understood. Understanding the molecular mechanisms that regulate invasion and disease spread would help to identify promising therapeutic targets and could be exploited to refine patient selection for already existing therapies.MicroRNAs (miRNAs) are small endogenous noncoding RNAs that negatively regulate mRNA stability and/or repress mRNA translation (7). miRNAs have been proven to play essential roles in the initiation and progression of certain cancer types, such as chronic lymphocytic leukemia (8), breast cancer (9), and lung cancer (10, 11). Several miRNA expression profiling studies have shown that miRNAs could be used as diagnostic and prognostic biomarkers. For example, high expression levels of miR-155 and low levels of let-7a expression correlate with poor prognosis of lung cancer (10). In colorectal cancer (CRC), up-regulated miR-135b correlates with tumor stage and poor clinical outcome (12). Recently, we conducted genome-wide miRNA sequencing in primary lung cancer tissue from patients with lung adenocarcinoma (ADC), and we identified that miR-31 promotes lymph node metastasis and negatively correlates with survival in patients with lung ADC (13), emphasizing the impact of miRNAs in NSCLC biology.TNFα-induced protein 1 (TNFAIP1) was originally identified as a TNFα- and LPS-inducible gene (14). It has been reported that TNFAIP1 interacts with the proliferating cell nuclear antigen and the small subunit of DNA polymerase-δ (P50) (15), suggesting that TNFAIP1 might be involved in DNA synthesis and apoptosis. Indeed, TNFAIP1 elicited proapoptotic activity, and coexpression of TNFAIP1 and RhoB markedly increased apoptosis in HeLa cells (16). SMAD4 plays a central role in the TGF-β family signaling pathways and is the only member of the SMAD family that is involved in TGF-β, activing, and bone morphogenetic protein signaling pathways (17, 18). SMAD4 functions as a tumor suppressor; loss of SMAD4 was frequently seen in pancreatic cancers and CRCs. Approximately 55% of pancreatic cancers have deletions or mutations in the SMAD4 locus (19), and about 30% of biallelic loss of SMAD4 was found in metastatic CRCs (20). To date, several studies have reported that TNFAIP1 and SMAD4 are targets of miRNAs in certain cancer types. For instance, oncogenic miRNAs, such as the miR-130a/301a/454 family, target SMAD4 in CRC, and miR-182 targets SMAD4 in bladder cancer (21, 22). In gastric cancer, miR-372/373 targets TNFAIP1, promoting carcinogenesis (23, 24).Here, we show that increased miR-224 in NSCLC promotes cell migration, invasion, and proliferation by direct targeting of TNFAIP1 and SMAD4. We further show that aberrant miR-224 expression is partially controlled by hypomethylation of its promoter region and activated ERK signaling in NSCLC. Through both in vitro and in vivo analyses, we revealed the mechanisms of miR-224 up-regulation and its oncogenic role in NSCLC pathogenesis.     

Epigenetic aberrant methylation of tumor suppressor genes in small cell lung cancer

Small cell lung cancer (SCLC), a special type of lung cancer, is reputed to carry a poor prognosis. The morbidity of SCLC is increasing in China and other countries. A variety of DNA alterations associated with non-small cell lung cancer (NSCLC) have been described. However, genetic and epigenetic changes of SCLC are not well established. Few studies have demonstrated that epigenetic silencing of key tumor suppressor genes (TSGs) is pivotal to initiation and development of SCLC. Recently, promoter methylation of many TSGs have been identified in SCLC. These novel TSGs are potential tumor biomarkers for early diagnosis and prognostic prediction. Moreover, epigenetic promoter methylation of TSGs could be a target of intervention with a wide prospect of clinical application. This review summarizes recent studies on promoter methylation of TSGs in SCLC and aims to provide better understanding of the promoter methylation in tumorigenesis and progression of SCLC.KEY WORDS : Small cell lung cancer (SCLC), tumor suppressor gene (TSG), promotor methylation, hypermethylation     

miR-874 Inhibits cell proliferation,migration and invasion through targeting aquaporin-3 in gastric cancer

Background

Aquaporin-3 (AQP3) is a water transporting protein which plays an oncogenic role in several malignant tumors. However, its regulatory mechanism remains elusive to date. In this study, we investigated the microRNA-mediated gene repression mechanism involved in AQP3's role.

Methods

The potential microRNAs targeting AQP3 were searched via bioinformatic methods and identified by luciferase reporter assays, microRNA RT–PCR and western blotting. The expression patterns of miR-874 and AQP3 in human gastric cancer (GC) specimens and cell lines were determined by microRNA RT-PCR and western blotting. 5-ethynyl-2′-deoxyuridine, cell migration and invasion assays and tumorigenicity in vivo were adopted to observe the effects of miR-874 depletion or ectopic miR-874 expression on GC cell phenotypes. Cell apoptosis was evaluated by FACS and TUNEL in vitro and in vivo respectively.

Results

miR-874 suppressed AQP3 expression by binding to the 3′UTR of AQP3 mRNA in GC cells. miR-874 was significantly down-regulated and reversely correlated with AQP3 protein levels in clinical samples. Analysis of the clinicopathological significance showed that miR-874 and AQP3 were closely correlated with GC characteristics. Functional analyses indicated that ectopic miR-874 expression suppressed the growth, migration, invasion and tumorigenicity of GC cells, whereas miR-874 knockdown promoted these phenotypes. Down-regulation of Bcl-2, MT1-MMP, MMP-2 and MMP-9 and upregulation of caspase-3 activity and Bax were involved in miR-874 inducing cell apoptosis, and inhibiting migration and invasion.

Conclusions

These results provide a mechanism by which AQP3 is upregulated, as well as highlight the importance of miR-874 in gastric cancer development and progression.     

miR-618在非小细胞肺癌中的表达及临床意义

目的探讨微小RNA-618(miR-618)在非小细胞肺癌(NSCLC)中的表达水平及临床意义。方法收集2012年1月-2014年1月我院NSCLC患者手术标本85例,采用实时荧光定量PCR(qRT-PCR)检测miR-618在85例NSCLC组织和其配对的癌旁组织中的表达水平,Kaplan-Meier法绘制生存曲线,Log Rank检验分析高低表达水平组的生存率差异。分析miRNA-618的表达水平与NSCLC临床病理参数的关系;多因素Logistic回归分析miRNA-618表达水平的影响因素。结果miRNA-618在NSCLC组织中的表达为(0.78±0.48),显著低于癌旁组织中的表达水平(0.99±0.57)(P<0.05)。miR-618低表达的NSCLC患者的术后5年总生存率为15.22%(7/46),显著低于miR-618高表达的NSCLC患者的33.33%(13/39)。miR-618低表达组中位OS(<28个月),低于miR-618高表达组中位OS(>36个月)(P<0.05)。miR-618在NSCLC组织中的表达水平与患者的年龄、性别、组织类型无关(P>0.05),与肿瘤大小、分化程度、TNM分期和淋巴结转移有关(P<0.05)。Logistic回归显示:肿瘤大小、分化程度、TNM分期和淋巴结转移是miR-618表达的显著影响因素(P<0.05)。结论miRNA-618在NSCLC中表达下调,其表达与NSCLC发生发展、预后有关,miR-618可作为NSCLC诊断和预后预测新的靶点。     

Estrogen and antiestrogen regulation of cell cycle progression in breast cancer cells

The central involvement of estrogen in the development of the mammary gland and in the genesis of breast cancer has lent impetus to studies of the links between estrogen action and the cell cycle machinery. Recent studies of the estrogenic regulation of molecules with known roles in the control of G1/S phase progression have resulted in significant advances in understanding these links. Estrogens independently regulate the expression and function of c-Myc and cyclin D1 and the induction of either c-Myc or cyclin D1 is sufficient to recapitulate the effects of estrogen on cell cycle progression. These pathways converge at the activation of cyclin E-Cdk2 complexes. The active cyclin E-Cdk2 complexes are depleted of the cyclin dependent kinase (CDK) inhibitor p21(WAF1/CIP1) because of estrogen-mediated inhibition of nascent p21(WAF1/CIP1). Insulin and estrogen synergistically stimulate cell cycle progression, and the ability of estrogen to antagonize an insulin-induced increase in p21(WAF1/CIP1) gene expression appears to underlie this effect. Antiestrogen treatment of MCF-7 cells leads to an acute decrease of c-Myc expression, a subsequent decline in cyclin D1, and ultimately arrest of cells in a state with features characteristic of quiescence. An antisense-mediated decrease in c-Myc expression results in decreased cyclin D1 expression and inhibition of DNA synthesis, mimicking the effects of antiestrogen treatment and emphasizing the importance of c-Myc as an estrogen/antiestrogen target. These data identify c-Myc, cyclin D1, p21(WAF1/CIP1) and cyclin E-Cdk2 as central components of estrogen regulation of cell cycle progression and hence as potential downstream targets that contribute to the role of estrogen in oncogenesis.     

小细胞肺癌规范化治疗及其进展

小细胞肺癌（small cell lung cancer，SCLC）发病率占肺癌的15％-20％，近年来欧美国家的发病率有所下降，我国目前尚无SCLC的临床流行病学资料。SCLC易发生血行转移，确诊时约2／3有远处转移，80％以上为胸腔内转移，故SCLC系全身性疾病已成不争的事实。SCLC对化放疗敏感，大部分患者初治效佳，但一旦复发转移，即产生继发性耐药，因此其5年总生存率低于非小细胞肺癌（NSCLC）。美国退伍军人分期将SCLC分为限局期与广泛期，前者肿瘤局限于一侧胸腔，包括纵隔、对侧肺门及双侧锁骨上淋巴结转移；后者肿瘤超出以上范围，包括恶性胸腔、心包积液及远处转移。近年来二者在治疗策略及方案上均有一定进展。     

miR-1290 is a potential prognostic biomarker in non-small cell lung cancer

Background

miR-1290 is a newly discovered microRNA (miRNA), and its role in non-small cell lung cancer (NSCLC) remains unknown. This study aimed to evaluate the expression levels of miR-1290 in NSCLC tissues and serum, and explore its associations with clinicopathological characteristics and prognosis of NSCLC patients.

Methods

A total of 33 pairs of tissues and 73 serum samples were obtained from NSCLC patients and expression levels of miR-1290 were detected by specific TaqMan qRT-PCR. The relationship between miR-1290 expression levels in NSCLC tissues and serum and clinicopathological characteristics was estimated respectively. The correlation between serum miR-1290 expression levels and overall survival of NSCLC patients was performed by Kaplan-Meier analysis and Cox proportional hazards model.

Results

We determined that miR-1290 expression levels were increased significantly in NSCLC tissues compared with non-tumor adjacent normal tissues, and higher miR-1290 expression levels were positively correlated with high tumor stage (P=0.004) and positive lymph node metastasis (P=0.013). Compared with benign lung disease and healthy controls, serum levels of NSCLC patients exhibited higher expression of miR-1290. Furthermore, the up-regulation of serum miR-1290 more frequently occurred in NSCLC patients with high TNM stage, positive lymph node metastasis (P=0.022 and P=0.024, respectively). Kaplan-Meier analysis demonstrated that high serum miR-1290 expression levels predicted poor survival (P=0.022). Cox proportional hazards risk analysis indicated that miR-1290 was an independent prognostic factor for NSCLC.

Conclusions

Our study suggests that miR-1290 is overexpressed in NSCLC, and serum miR-1290 may be used as a potential prognostic biomarker for NSCLC.     

Differential TIMP3 expression affects tumor progression and angiogenesis in melanomas through regulation of directionally persistent endothelial cell migration

The angiogenic potential of solid tumors, or the ability to initiate neovasculature development from pre-existing host vessels, is facilitated by soluble factors secreted by tumor cells and involves breaching of extracellular matrix barriers, endothelial cell (EC) proliferation, migration and reassembly. We evaluated the angiogenic potential of human melanoma cell lines differing in their degree of aggressiveness, based on their ability to regulate directionally persistent EC migration. We observed that conditioned-medium (CM) of the aggressive melanoma cell line BLM induced a high effective migratory response in ECs, while CMs of Mel57 and 1F6 had an inhibitory effect. Further, the melanoma cell lines exhibited a varied expression profile of tissue inhibitor of metalloproteinase-3 (TIMP3), detectable in the CM. TIMP3 expression inversely correlated with aggressiveness of the melanoma cell line, and ability of the respective CMs to induce directed EC migration. Interestingly, TIMP3 expression was found to be silenced in the BLM cell line, concurrent with its role as a tumor suppressor. Treatment with recombinant human TIMP3 and CM of modified, TIMP3 expressing, BLM cells mitigated directional EC migration, while CM of TIMP3 silenced 1F6 cells induced directed EC migration. The functional implication of TIMP3 expression on tumor growth and angiogenic potential in melanoma was evaluated in vivo. We observed that TIMP3 expression reduced tumor growth, angiogenesis and macrophage infiltration of BLM tumors while silencing TIMP3 increased tumor growth and angiogenesis of 1F6 tumors. Taken together, our results demonstrate that TIMP3 expression correlates with inhibition of directionally persistent EC migration and adversely affects the angiogenic potential and growth of melanomas.     

Coriolus versicolor polysaccharide peptide slows progression of advanced non-small cell lung cancer

BACKGROUND: Non-small cell lung cancer (NSCLC) is a leading cause of cancer deaths, and over 60% of patients present with advanced stages. Although polysaccharide peptides (PSP), isolated from the fungus Coriolus versicolor, have been reported to have anti-tumor effects, its clinical efficacy has not been properly evaluated. METHODS: Double-blind placebo-controlled randomized study to evaluate the effects of 28-day administration of PSP (Windsor Pharmaceutical, Hong Kong) on patients, who had completed conventional treatment for advanced NSCLC. RESULTS: Thirty-four patients, with no significant difference in their baseline demographic, clinical or tumor characteristics, or previous treatment regimes (P>0.05) were recruited into each of the PSP and control arms. After 28-day treatment, there was a significant improvement in blood leukocyte and neutrophil counts, serum IgG and IgM, and percent of body fat among the PSP, but not the control, patients (P<0.05). Although the evaluable PSP patients did not improve in NSCLC-related symptoms, there were significantly less PSP patients withdrawn due to disease progression, than their control counterparts (5.9 and 23.5%, respectively; P=0.04; OR 4.00). There was no reported adverse reaction attributable to the trial medications. CONCLUSION: PSP treatment appears to be associated with slower deterioration in patients with advanced NSCLC.