Mechanisms involved in lung cancer development in COPD

Lung cancer and chronic obstructive pulmonary disease (COPD) are leading causes of morbidity and mortality worldwide. They share a common environmental risk factor in cigarette smoke exposure and a genetic predisposition represented by the incidence of these diseases in only a fraction of smokers. COPD is also a major independent risk factor for lung carcinoma, among long-term smokers. Smokers with COPD also have a higher risk of developing a specific histological subtype of non-small cell lung cancer termed squamous cell carcinoma. For these reasons the focus of this review is on the potential pathogenic molecular links between tobacco smoking-related COPD and squamous cell carcinoma. We believe that we need to promote more studies on the molecular and cellular pathobiology of smokers with premalignant bronchial lesions of the squamous cell lung carcinoma compared with a control group of smokers with and without COPD to unravel the complex molecular interactions between COPD and early squamous cell lung carcinoma. These studies should also look at younger healthy smokers in combination with risk models of lung cancer and COPD. Overall these studies may allow the discovery of new molecular targets of the early carcinogenesis process that in the foreseeable future may render the early diagnosis and treatment, and may be even the prevention, of invasive squamous cell lung carcinoma a reality.     

A novel adamantane thiadiazole derivative induces mitochondria-mediated apoptosis in lung carcinoma cell line

The interaction of organic compounds with apoptosis regulatory proteins is an attractive field of research because of its relevance in the development of new chemotherapeutic agents for cancer treatment. Our group designed four new adamantane thiadiazole derivatives (ATDs). The four ATDs were theoretically tested for their binding affinities to a model of an apoptosis inhibitor protein using molecular modeling. ATD-4 which interacted with the highest binding affinity was synthesized and characterized. The in vitro cytotoxicity of ATD-4 against different cancer cell lines as well as normal cell line was determined and compared with 5-fluorouracil as a standard positive control. The lung carcinoma cell line that showed the highest cytotoxic activity due to ATD-4 treatment was chosen to further study if ATD-4 can perform its cytotoxic activity through the induction of apoptosis as expected from molecular modeling. Inducing apoptosis by ATD-4 in lung carcinoma cell line was assessed by various biochemical and morphological characteristics. Biochemically: The effect of ATD-4 on cell cycle and its ability to induce apoptosis were checked through flow cytometry. Caspase-3 activity was detected by a colorimetric method. Real time-polymerase chain reaction (q-PCR) was used to detect p53, caspase-3, bcl-2 and bax gene expression. Morphologically: Changes in cell surface morphology, granulation and average surface roughness were detected using atomic force microscopy (AFM). Cell shrinkage, increase in cytoplasmic organelles, changes in mitochondrial number and morphology, chromatin condensation, membrane blebbing and formation of apoptotic bodies were detected using transmission electron microscopy (TEM). The obtained results suggest that ATD-4 exerted its antitumor activity against A549 cells through the induction of the intrinsic (mitochondrial) apoptotic pathway.     

基于多组学数据的早期宫颈鳞状细胞癌分类

从分子层面对泛癌进行研究已经得到了很大的进展,但是对宫颈鳞状细胞癌的分子分类研究仍然需要更多的探索.为了找到宫颈鳞状细胞癌潜在的子类,本文提出了一个基于多维组学数据的癌症亚型分类分析流程.通过统计学方法对癌症基因组图谱(The Cancer Genome Atlas,TCGA)宫颈鳞状细胞癌的mRNA表达数据、小分子核糖核酸(microRNA,miRNA)表达数据、DNA甲基化数据以及拷贝数变异数据4个维度包含的分子进行筛选,然后对筛选后的分类特征进行整合聚类,进一步筛选能够区分不同子类的关键分类特征,并使用这些关键分类特征建立宫颈鳞状细胞癌分类模型.本研究为宫颈鳞状细胞癌分子层面子类的识别提供了分析流程,得到了两个临床生存水平具有显著性差异的宫颈鳞状细胞癌子类,并确定了8个宫颈鳞状细胞癌的关键分类特征.本研究中识别的宫颈鳞状细胞癌子类和关键分类特征为宫颈鳞状细胞癌早期分类及分类标志物的鉴定提供了重要参考.     

Cell death: programmed, apoptosis, necrosis, or other?

There are at least two major types of active or physiological cell death. The most well-known form, apoptosis or Type I, involves early nuclear collapse, condensation of chromatin, generation of nucleosomal ladders, and cell fragmentation with little or no early alteration of lysosomes. It is most commonly seen in cells deriving from highly mitotic lines, and the cells are phagocytosed by neighboring cells or infiltrating macrophages. In metamorphosing or secretory cells, and under conditions where the majority of cells die, the bulk of the cytoplasm is consumed by expansion of the lysosomal system well before nuclear collapse is manifest. This form of cell death has been termed Type II cell death, and we revert to this terminology. The requirement for protein synthesis is more characteristic of Type II cell death in developmental situations than it is for Type I cell death. The variations seen force a reassessment of those aspects of physiological cell death that are truly universal, thereby focusing attention on the biology of the process. A better understanding of the biology and morphology of dying cells will help clarify the significance of the molecular and biochemical findings.     

FilGAP,a Rho/Rho-associated protein kinase–regulated GTPase-activating protein for Rac,controls tumor cell migration

Tumor cells exhibit two interconvertible modes of cell motility referred to as mesenchymal and amoeboid migration. Mesenchymal mode is characterized by elongated morphology that requires high GTPase Rac activation, whereas amoeboid mode is dependent on actomyosin contractility induced by Rho/Rho-associated protein kinase (ROCK) signaling. While elongated morphology is driven by Rac-induced protrusion at the leading edge, how Rho/ROCK signaling controls amoeboid movement is not well understood. We identified FilGAP, a Rac GTPase-activating protein (GAP), as a mediator of Rho/ROCK-dependent amoeboid movement of carcinoma cells. We show that depletion of endogenous FilGAP in carcinoma cells induced highly elongated mesenchymal morphology. Conversely, forced expression of FilGAP induced a round/amoeboid morphology that requires Rho/ROCK-dependent phosphorylation of FilGAP. Moreover, depletion of FilGAP impaired breast cancer cell invasion through extracellular matrices and reduced tumor cell extravasation in vivo. Thus phosphorylation of FilGAP by ROCK appears to promote amoeboid morphology of carcinoma cells, and FilGAP contributes to tumor invasion.     

Cisplatin resistance can be curtailed by blunting Bnip3-mediated mitochondrial autophagy

Cisplatin (CDDP) is commonly used to treat a multitude of tumors including sarcomas, ovarian and cervical cancers. Despite recent investigations allowed to improve chemotherapy effectiveness, the molecular mechanisms underlying the development of CDDP resistance remain a major goal in cancer research. Here, we show that mitochondrial morphology and autophagy are altered in different CDDP resistant cancer cell lines. In CDDP resistant osteosarcoma and ovarian carcinoma, mitochondria are fragmented and closely juxtaposed to the endoplasmic reticulum; rates of mitophagy are also increased. Specifically, levels of the mitophagy receptor BNIP3 are higher both in resistant cells and in ovarian cancer patient samples resistant to platinum-based treatments. Genetic BNIP3 silencing or pharmacological inhibition of autophagosome formation re-sensitizes these cells to CDDP. Our study identifies inhibition of BNIP3-driven mitophagy as a potential therapeutic strategy to counteract CDDP resistance in ovarian carcinoma and osteosarcoma.Subject terms: Cancer therapeutic resistance, Mitophagy     

Alteration in tryptic peptide patterns of ferritins purified from human colon carcinoma

Ferritin from malignant tissue differs electrophoretically from normal ferritin. The molecular basis of this difference has not yet been defined. Malignant tissue contains a mixture of ferritins from normal cells, inflammatory cells as well as cancer cells. GW-39 is a pure colon carcinoma cell system that synthesizes human carcinoembryonic antigen. Therefore, ferritin was isolated from normal colon mucosa and colon cancer tissues, as well as from the colon carcinoma cell line, to clarify the molecular relationship between normal and malignant ferritins. Colon carcinoma ferritin differs in primary structure from normal colon mucosal ferritin and contains at least six additional different tryptic peptides. These six peptides were also found in the ferritin from the colon carcinoma cell line. These data suggest that the alteration in ferritin structure occurs at the cellular level and is associated with the malignant state.     

New Insights into Syndecan-2 Expression and Tumourigenic Activity in Colon Carcinoma Cells

Adhesion receptors play crucial roles in the neoplastic transformation of normal cells through induction of cancer-specific cellular behaviour and morphology. This implies that cancer cells likely express and utilize a distinct set of adhesion receptors during carcinogenesis. Colon cancer is an excellent model system for the study of this process, since both molecular genetic and morphological changes have been well established for this disease. We recently reported increased expression of the cell surface adhesion receptor, syndecan-2, in several colon carcinoma cell lines. Indeed, increased syndecan-2 expression was necessary for tumourigenic activity, suggesting that syndecan-2 might have value as both a new diagnostic marker and a possible therapeutic target. Here, we review recent advances in understanding the role of syndecan-2 in the carcinogenesis of colon cells, and discuss a leading role for this molecule in a new era for colon cancer treatment.     

The oncostatin M signalling pathway: reversing the neoplastic phenotype?

Oncostatin M (OSM) is a member of the interleukin 6 (IL-6) family of cytokines and was originally identified by its ability to inhibit proliferation of melanoma cells but augment the growth of normal fibroblasts. OSM has pleiotropic effects on many different cell types, but here we focus on its ability to inhibit the proliferation of cell lines derived from several tumour types, including breast carcinoma, ovarian cancer, melanoma, glioma and lung carcinoma. The inhibition of proliferation of several cancer cell lines by OSM is associated with alterations in cellular morphology and with phenotypic changes that are consistent with the induction of differentiation of these cells. These observations raise the possibility that OSM could have therapeutic potential.     

Effects of Carvacrol on a Human Non-Small Cell Lung Cancer (NSCLC) Cell Line, A549

Carvacrol, the predominant monoterpene in many essential oils of Labitae including Origanum, Satureja, Thymbra, Thymus, and Corydothymus has substantial antibacterial, antifungal, antihelmintic, insecticial, analgesic and antioxidant activities. Approximately 75% of lung cancer is non-small cell carcinoma (NSCLC) which comprises several histologic types squamous cell, adenocarcinoma and large cell carcinoma. It was reported that the portion of lung tumors diagnosed as denocarcinoma has increased. Thus a human non-small cell lung cancer (NSCLC) cell line, A549 was chosen for this study. To investigate the effects of carvacrol on cell morphology, apoptosis and total protein amount, the cells incubated with various concentration of carvacrol in DMSO for 24 h. In carvacrol applied A549 cell line, increase in dose of carvacrol caused a decrease in cell number, degeneration of cell morphology and a decrease in total protein amount. To characterize carvacrol induced changes in cell morphology, cells were examined by light microscopy. Cells were treated with carvacrol were seen to have detached from the disk, with cell rounding, cytoplasmic blebbing and irregularity in shape. The data demonstrate that carvacrol is very potent inhibitor of cell growth in A549 cell line.     

Current concepts in ovarian epithelial tumorigenesis: correlation between morphological and molecular data

Ovarian carcinoma is the most lethal gynaecological malignancy, most tumours being advanced at presentation. However, little is known about precursor lesions and the cell of origin of epithelial ovarian malignancy. In this review, the proposed cell of origin is discussed as well as recent molecular data relating to ovarian cancers of different morphological types. It is stressed that ovarian carcinoma is a heterogeneous group of neoplasms with several different morphological types, each with their own underlying molecular genetic events. Recent data suggest that mucinous ovarian cancers and a small subset of serous cancers (low grade ovarian serous carcinoma) develop through a well-defined adenoma-carcinoma sequence while the much more common high grade ovarian serous carcinoma develops de novo from the ovarian surface epithelium or the epithelium of cortical inclusion cysts. The realisation that various morphological types of epithelial ovarian cancer are associated with different molecular genetic events is a major advance in the study of ovarian cancer. It can be anticipated that this will lead to the development of specific therapeutic agents of value against a specific tumour type.     

Isolation and characterization of a novel human bladder cancer cell line: BK10

Summary Molecular studies of bladder carcinomas have aided in determining causative genetic events and the prognosis of cancers endowed with certain abnormalities. In vitro bladder cancer characterization of key cytogenetic alterations is useful for study of molecular changes that may promote oncogenic events. In our laboratory, a novel human bladder cancer cell line, BK10, has been established in vitro and passaged for more than 20 mo. This new bladder cancer cell line (BK10) was derived from bladder tissue containing grade III-IV/IV transitional cell carcinoma. Bladder cancer tissue was obtained at the time of radical cystoprostatectomy extirpation. Cell cultures derived from this surgical sample exhibited an epithelial morphology and expressed epithelial cytokeratins. Immunostains of BK10 were negative for prostate specific antigen (PSA), fibronectin, smooth muscle actin alpha, and desmin. Karyotypic analysis revealed an aneuploid chromosomal content 〈4n〉 with many numerical and structural abnormalities previously linked to bladder oncogenesis. Translocations occurred in chromosomes 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 13, 14, 15, 16, 17, 19, 20, 21, 22, X and Y. G-banding analysis revealed rearrangements involving chromosomes 9q and 17p, and the location of the ab11 oncogene and the p53 gene, respectively. The availability of this bladder cancer cell line will provide a useful too for the further study of bladder carcinoma oncogenesis and gene therapy.     

环氧合酶-2在胃癌中的研究进展

我国胃癌发病人数居全球首位,其发生机制及安全有效的治疗是研究重点。大量研究结果表明,环氧化酶-2(Cyclooxygenase-2,COX-2)过度表达促进肿瘤细胞增殖和抑制细胞凋亡,并与胃癌的发生发展、淋巴转移、分化程度、病理分期及预后密切相关。随着COX-2与胃癌关系的研究的深入,COX-2已逐渐成为胃癌治疗的新的靶点。近年来,针对细胞受体、信号传导、细胞周期和血管生成等靶点的抗肿瘤治疗已成为肿瘤治疗研究的新方向。因此,以COX-2为特异靶点的治疗策略有望为胃癌治疗提供新的思路。     

Can cytology reliably subtype non-small cell lung carcinomas?

Cytology specimens play an important role in the diagnosis and predictive testing of lung cancer. While morphological characterisation of small cell and non-small cell lung carcinomas (NSCLC) on cytology is possible, further subtyping of NSCLC into adenocarcinoma and squamous cell carcinoma morphology is also mandatory in the current era of personalised medicine. Notably, cytology specimens in different forms (fine needle aspiration, exfoliative, and cell block) with or without immunocytochemistry are reliable sources for accurate diagnosis of adenocarcinoma and squamous cell carcinoma as evidenced by numerous studies present in the literature. However, there are instances where subtyping of NSCLC based on morphology alone is challenging on cytology samples, especially non-cell block preparations. In this paper, we will discuss current concepts, advances, and challenges of subtyping NSCLC in cytology specimens.     

Agrin and Perlecan Mediate Tumorigenic Processes in Oral Squamous Cell Carcinoma

Oral squamous cell carcinoma is the most common type of cancer in the oral cavity, representing more than 90% of all oral cancers. The characterization of altered molecules in oral cancer is essential to understand molecular mechanisms underlying tumor progression as well as to contribute to cancer biomarker and therapeutic target discovery. Proteoglycans are key molecular effectors of cell surface and pericellular microenvironments, performing multiple functions in cancer. Two of the major basement membrane proteoglycans, agrin and perlecan, were investigated in this study regarding their role in oral cancer. Using real time quantitative PCR (qRT-PCR), we showed that agrin and perlecan are highly expressed in oral squamous cell carcinoma. Interestingly, cell lines originated from distinct sites showed different expression of agrin and perlecan. Enzymatically targeting chondroitin sulfate modification by chondroitinase, oral squamous carcinoma cell line had a reduced ability to adhere to extracellular matrix proteins and increased sensibility to cisplatin. Additionally, knockdown of agrin and perlecan promoted a decrease on cell migration and adhesion, and on resistance of cells to cisplatin. Our study showed, for the first time, a negative regulation on oral cancer-associated events by either targeting chondroitin sulfate content or agrin and perlecan levels.     

Molecular diagnostics of non-small cell lung cancer using mediastinal lymph nodes sampled by endoscopic ultrasound-guided needle aspiration

Non-small cell lung cancer is a common cancer with significant mortality. Accurate and early staging of this cancer has a significant impact on outcome. Endoscopic ultrasound-guided fine needle aspiration of involved mediastinal lymph nodes is critical for staging. Several molecular markers have been identified recently in association with non-small cell carcinoma of the lung that are promising to make early detection of metastatic disease more reliable.     

Raloxifene,a mixed estrogen agonist/antagonist,induces apoptosis through cleavage of BAD in TSU-PR1 human cancer cells

Selective estrogen receptor modulator is a proven agent for chemoprevention and chemotherapy of cancer. Raloxifene, a mixed estrogen agonist/antagonist, was developed to prevent osteoporosis and potentially reduce the risk of breast cancer. In this study, we examined the effect of raloxifene on the TSU-PR1 cell line. This cell line was originally reported to be a prostate cancer cell line, but recently it has been shown to be a human bladder transitional cell carcinoma cell line. The TSU-PR1 cell line contains high levels of estrogen receptor beta. Following treatment with raloxifene, evidence of apoptosis, including change in nuclear morphology, DNA fragmentation, and cytochrome c release, was observed in a dose-dependent manner in the TSU-PR1 cells (10(-9) to 10(-6) m range). We observed no detectable change in the steady-state levels of Bax, Bcl-2, and Bcl-X(L) following raloxifene treatment. However, raloxifene induced caspase-dependent cleavage of BAD to generate a 15-kDa truncated protein. Overexpression of a double mutant BAD resistant to caspase 3 cleavage blocked raloxifene-induced apoptosis. These results demonstrate that raloxifene induces apoptosis through the cleavage of BAD in TSU-PR1 cells. This molecular mechanism of apoptosis suggests that raloxifene may be a therapeutic agent for human bladder cancer.