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Recent cancer research has more strongly emphasized the biophysical aspects of tumor development, progression, and microenvironment. In addition to genetic modifications and mutations in cancer cells, it is now well accepted that the physical properties of cancer cells such as stiffness, electrical impedance, and refractive index vary with tumor progression and can identify a malignant phenotype. Moreover, cancer heterogeneity renders population-based characterization techniques inadequate, as individual cellular features are lost in the average. Hence, platforms for fast and accurate characterization of biophysical properties of cancer cells at the single-cell level are required. Here, we highlight some of the recent advances in the field of cancer biophysics and the development of lab-on-a-chip platforms for single-cell biophysical analyses of cancer cells.

Neurensin-2 (NRSN2) is a 24KD protein, which is reported located in the membrane, while its biological functions remain unknown, not to mention in the field of tumor biology. In current study, we aimed to analyze the functions of NRSN2 in ovarian cancer. We screened TCGA database and surprisingly found that its copy number and mRNA level are gained and heightened respectively in parts of serous ovarian cancer patients. In current study, both loss- and gain- function assays found that NRSN2 is associated with the malignant phenotype in ovarian cancer cells, because NRSN2 plays a remarkable role in anchorage-independent colony formation, subcutaneous tumor formation, cell invasion, and chemoresistance. Furthermore, we found that the level of NRSN2 was positively correlated with the expression of stem cell marker CD133. In addition, Wnt canonical signaling and Twist/Akt/Erk axis were also regulated by NRSN2. In conclusion, we found that a poorly studied protein, NRSN2, which is associated with the malignant phenotype of serous ovarian cancer and as a membrane protein; it could be a target for serous ovarian cancer treatment.

Introduction: Glioma is the most common malignant tumor in the brain. Alternative splicing can lead to a malignant phenotype of glioma, which is expected to be a target for glioma treatment. Material and Methods: Expression data and alternative splicing events of glioma were downloaded from the TCGA and TCGASpliceSeq database. Cox regression was used to analyze prognosis-associated AS events. Results: Prognosis-associated alternative splicing events were identified and the prognostic model for glioma was constructed, which have good prognostic abilities for glioma. Conclusion: The identified prognosis-associated alternative splicing events may provide experimental directions and targets for the alternative splicing study of glioma. Funding: Not applicable. Declaration of Interest: The authors declare there are no conflicts of interest.

One of the defining characteristics of the malignant phenotype is the ability to evade the host immune system. Immunotherapy as a treatment modality represents a new dawn in the way we think about the treatment of a variety of malignancies. The story of immunotherapy traces its roots to its relationship with malignant melanoma. In this article, we review the intertwined history of immunotherapy and melanoma, including the early significant history, a discussion on immune mechanisms, resistance, local and systemic immunotherapeutic modalities, and speculate on possible novel future treatment options.

A precise stratification of our patients is essential and can support clinicians to determine the right therapy. The aim of this study was to identify clinically relevant genes using The Cancer Genome Atlas (TCGA) datasets. A comprehensive pan-cancer analysis of 30 distinct tumor entities (N = 9022) identified the largely unknown gene Downstream neighbor of SON (DONSON) to be particularly associated with unfavorable overall survival in clear cell renal cell carcinoma (KIRC). This prognostic potential of DONSON was validated in an independent KIRC cohort via quantitative real-time PCR (n = 152). Further, DONSON protein expression was evaluated via immunohistochemical staining followed by quantitative image analysis using the image analysis software QuPath on a renal cancer tissue microarray (n = 270). Interestingly, DONSON overexpression was preferentially associated with poor survival in 9 of the 30 entities, suggesting tumor-independent oncogenic properties of this largely unknown gene. A particularly strong association of DONSON to an aggressive phenotype was evident in KIRC and proved to be a strong independent predictor of unfavorable overall survival in two additional cohorts on the mRNA and protein level. In our KIRC cell culture model, we observed a substantial attenuation of proliferative activity and migration capacity of the KIRC cells Caki1 and 769p. In conclusion, we identified DONSON as a robust biomarker for risk stratification in KIRC in three independent cohorts and provide evidence that DONSON is linked to a malignant phenotype in the KIRC cell culture model.

Bromopyruvate (3-BrPA) is a glycolysis inhibitor that has been reported to have a strong anti-tumour effect in many human tumours. Several studies have reported that 3-BrPA could inhibit glioma progression; however, its role on the interstitial cells in the glioma microenvironment has not been investigated. In previous studies, we found that in the glioma microenvironment, glioma stem cells can induce the malignant transformation of macrophages and dendritic cells. In this study, we focused on the effects of 3-BrPA on malignantly transformed macrophages and dendritic cells. First, we found that 3-BrPA inhibited the proliferation of malignantly transformed macrophages and dendritic cells in a dose-dependent and time-dependent manner. Further study indicated that 3-BrPA significantly decreased extracellular lactate and inhibited the clone formation, migration and invasion of malignantly transformed macrophages and dendritic cells. Using an online database and a series of experiments, we demonstrated that 3-BrPA inhibits the malignant progression of malignantly transformed macrophages and dendritic cells via the miR-449a/MCT1 axis. These findings built experimental basis for new approach against glioma.

Human papillomaviruses (HPVs) infect the squamous epithelium and can induce benign and malignant lesions. To date, more than 200 different HPV types have been identified and classified into five genera, α, β, γ, μ, and ν. While high-risk α mucosal HPVs have a well-established role in cervical carcinoma and a significant percentage of other anogenital tract and oral carcinomas, the biology of the cutaneous β HPVs and their contribution to non-melanoma skin cancer (NMSC) has been less studied. Although the association of β HPV infection with NMSC in patients with a rare, genetically determined condition, epidermodysplasia verruciformis has been well established, the role of β HPV infection with NMSC in the normal population remains controversial. In stark contrast to α HPV-associated cancers, the presence of the β HPV genome does not appear to be mandatory for the maintenance of the malignant phenotype. Moreover, the mechanism of action of the β HPV E6 and E7 oncoproteins differs from the β HPV oncoproteins.

Malignant transformation of normal cells to cancer cells represents an enigmatic phenomenon because of the many ambiguous controversies embodied within most of its aspects. Within a clinical context, cancer, with very few exceptions, is a dreadful disease that ends lethally. Within a biological context, however, cancer is a peculiar biosystem that has its own rules that regulate the actions/interactions/structure and behavior of its components. Unfortunately, the majority of these rules are, still, unknown. The current disappointing situation as regards research trials aiming at constructing effective treatments for cancer might be attributed, in part, to incomplete recognition of the significant differences between these two contexts of malignant transformation. Although the peculiar characteristics of cancer as a self-dependent biosystem are well studied and well defined, the basic dilemma of malignant transformation continues to exist: we know, largely, how things happen but we do not know, to any extent, why they happen. Though the logic that motivates researches aiming at formulating genetic therapies for cancer is quite reasonable, as cancer is primarily a genetic alteration, lack of essential basic knowledge regarding the different aspects of this alteration adjourn successful radical cure of cancer. Till comprehensive disclosure of the underlying mechanisms regulating growth/progression/metastasis and survival of malignant cells is attained, treatments of cancer based on different strategic concepts, viz. proteomic therapies rather than genetic therapies, might, hopefully, be the best approaches available in the fight against cancer in the current as well as in the coming era. Keywords: Cancer; Temporal imprinting; Malignant transformation; Malignant phenotype; Genomic reprograming; Genomic involution; Evolutionary paradox; Metastasis; Oncoproteome; Cancer therapy; Oncogenome

Melanomas are among the most common skin tumors in horses, with prevalence rates reaching as high as 80% in adult gray horses. Most melanocytic tumors are benign at initial presentation; however, if left untreated, up to two-thirds can progress to overt malignant behavior. Standard local treatment options can be used to treat solitary early-stage lesions but do not address the underlying risk of recurrent tumor formation or the transformation to a malignant phenotype. An understanding of the specific molecular genetic factors associated with tumor formation should lead to targeted therapies that can be used to treat or ideally prevent disease.

The development of breast malignancy has been recognised to progress through a number of morphological precursor lesions. More recently, specific molecular alterations have been recognised in these precursor lesions. These changes appear to determine a specific malignant phenotype, which in turn, may realign the current opinion on the classification of breast cancer along molecular characteristics. This review will highlight the morphological features of these precursor lesions and their relationship to the complex molecular processes involved in their development.

A steadily growing number of studies have shown that microRNAs have key roles in the regulation of cellular processes and that their dysregulation is essential to keep the malignant phenotype of cancer cells. The distorted and unique expression profile of microRNAs in different types and subsets of tumor coupled with their presence in biological fluids make of microRNAs an attractive source of sensitive biomarkers. Here, we will discuss how microRNA profiles are altered in cancer, highlighting their potential as sensitive biomarkers for cancer risk stratification, outcome prediction and classification of histological subtypes. We will also evaluate the current knowledge on the use of microRNAs as circulating biomarkers, hoping that further studies will lead to the application of microRNA signature in prognostic and predictive markers that can improve patient health.

Knowledge gaps persist about the efficacy of cancer prevention strategies based on dietary food components. Adaptations to nutrient supply are executed through tuning of multiple protein networks that include transcription factors, histones, modifying enzymes, translation factors, membrane and nuclear receptors, and secreted proteins. However, the simultaneous quantitative and qualitative measurement of all proteins that regulate cancer processes is not practical using traditional protein methodologies. Proteomics offers an attractive opportunity to fill this knowledge gap and unravel the effects of dietary components on protein networks that impinge on cancer. The articles presented in this supplement are from talks proffered in the “Nutrition Proteomics and Cancer Prevention” session at the American Institute for Cancer Research Annual Research Conference on Food, Nutrition, Physical Activity and Cancer held in Washington, DC on October 21 and 22, 2010. Recent advances in MS technologies suggest that studies in nutrition and cancer prevention may benefit from the adoption of proteomic tools to elucidate the impact on biological processes that govern the transition from normal to malignant phenotype; to identify protein changes that determine both positive and negative responses to food components; to assess how protein networks mediate dose-, time-, and tissue-dependent responses to food components; and, finally, for predicting responders and nonresponders. However, both the limited accessibility to proteomic technologies and research funding appear to be hampering the routine adoption of proteomic tools in nutrition and cancer prevention research.

12(S)-Lipoxygenase (LOX) and its product 12(S)-hydroxyeicosatetraenic (HETE) acid have been implicated in angiogenesis and tumour invasion in several tumour types while their role in colorectal cancer progression has not yet been studied. We have analysed 12(S)-LOX expression in colorectal tumours and found gene expression up-regulated in colorectal cancer specimens for which the pathology report described involvement of inflammation. Using cell line models exposed to 12(S)-HETE or over-expressing 12(S)-LOX malignant cell growth as well as tumour cell migration was found to be stimulated. Specifically, Caco2 and SW480 cells over-expressing 12(S)-LOX formed fewer colonies from sparse cultures, but migrated better in filter-migration assays. SW480 LOX cells also had higher anchorage-independent growth capacity and a higher tendency to metastasise in vivo. Knock-down or inhibition of 12(S)-LOX inhibited cell migration and anchorage-independent growth in both 12(S)-LOX transfectants and SW620 cells that express high endogenous levels of 12(S)-LOX. On the cell surface E-cadherin and integrin-β1 expression were down-regulated in a 12(S)-LOX-dependent manner disturbing cell–cell interactions. The results demonstrate that 12(S)-LOX expression in inflammatory areas of colorectal tumours has the capacity to induce an invasive phenotype in colorectal cancer cells and could be targeted for therapy., Highlights ► 12(S)-LOX is up-regulated in inflammatory areas of colorectal tumours. ► 12(S)-HETE and 12(S)-LOX over-expression stimulate malignant growth and migration. ► 12(S)-LOX over-expressing SW480 cells have a higher tendency to metastasise. ► Blocking 12(S)-LOX activity or expression inhibits malignant growth and migration.

B-RAF, a serine–threonine protein kinase, is one of the three RAF paralogs in humans. B-RAF participates in the RAS-RAF-MEK-ERK pathway, a conserved protein kinase-signalling cascade that is involved in regulating a number of critical cellular functions. Mutated B-RAF is believed to play a crucial role in the development, maintenance and progression of melanoma, where it contributes to multiple aspects of the malignant phenotype, such as cell survival, proliferation and apoptosis resistance. Indeed, it is mutated in a high proportion of melanocytic skin lesions and B-RAF mutations are preserved through melanoma progression. Despite this, the direct inhibition of B-RAF has shown little success clinically in the treatment of melanoma, presumably due to the complexity of the RAS-RAF-MEK-ERK pathway. For this reason, alternative strategies must be developed to treat oncogenic B-RAF-induced melanomas.

The behaviour of cells cultured within three-dimensional (3D) structures rather than onto two-dimensional (2D) culture plastic more closely reflects their in vivo responses. Consequently, 3D culture systems are becoming crucial scientific tools in cancer cell research. We used a novel 3D culture concept to assess cell-matrix interactions implicated in carcinogenesis: a synthetic hydrogel matrix equipped with key biomimetic features, namely incorporated cell integrin-binding motifs (e.g. RGD peptides) and the ability of being degraded by cell-secreted proteases (e.g. matrix metalloproteases). As a cell model, we chose epithelial ovarian cancer, an aggressive disease typically diagnosed at an advanced stage when chemoresistance occurs. Both cell lines used (OV-MZ-6, SKOV-3) proliferated similarly in 2D, but not in 3D. Spheroid formation was observed exclusively in 3D when cells were embedded within hydrogels. By exploiting the design flexibility of the hydrogel characteristics, we showed that proliferation in 3D was dependent on cell-integrin engagement and the ability of cells to proteolytically remodel their extracellular microenvironment. Higher survival rates after exposure to the anti-cancer drug paclitaxel were observed in cell spheroids grown in hydrogels (40-60%) compared to cell monolayers in 2D (20%). Thus, 2D evaluation of chemosensitivity may not reflect pathophysiological events seen in patients. Because of the design flexibility of their characteristics and their stability in long-term cultures (28 days), these biomimetic hydrogels represent alternative culture systems for the increasing demand in cancer research for more versatile, physiologically relevant and reproducible 3D matrices. Copyright © 2010 Elsevier Ltd. All rights reserved.

Epithelial to mesenchymal transition (EMT) is a highly conserved programme of events essential for normal development. As it underpins cell plasticity, migration and invasion in a number of settings it is an attractive concept to apply to the malignant phenotype. Much is known about the molecular events regulating EMT in a number of model organisms, including Drosophila, sea urchin, zebrafish, xenopus and the chick. It is increasingly apparent that EMT is a highly conserved process, and that discoveries made in these systems provide excellent insights into the understanding of the role of EMT in human malignancies.

Vinyl carbamate (VC) is derived from ethyl carbamate (EC), a chemical found in alcoholic beverages and fermented foods. The objectives of this study were to characterize the formation of lung tumors induced by VC in F1 (Big BluexA/J) mice, and to identify the mutations formed in the Kras2 gene. In addition, we have tested the hypothesis that pretreatment with diallyl sulfone (DASO2) inhibits the adverse effects of VC. Mice were treated with VC (60 mg/kg, i.p.) or DASO2 (50 mg/kg, p.o.) 2 h prior to VC (DASO2/VC). Lung tumor multiplicity was significantly lower (21%) in mice treated with DASO2/VC than with VC. Lung tumors induced by VC are manifested as solid or papillary tumors, with the latter being regarded as a more malignant phenotype as they demonstrate no growth restrictions. Solid (42%) and papillary tumors (58%) were found in similar proportions in VC-treated mice. The number of papillary tumors was significantly decreased (44.5%) in mice treated with DASO2/VC, while there was a proportional increase (44.5%) in the number of solid tumors. The number of tumors with mutations in the first and second exon of Kras2 was significantly lower after treatment with DASO2/VC (7%) than after treatment with VC (61%). The mutations were mainly found in codon 61, and were identified as A-->T transversions (31%) and A-->G transitions (25%) in the second base, and A-->T transversions (12%) in the third base. All of these mutations were significantly reduced by DASO2 pretreatment. The number of tumors containing Kras2 mutations was highest (38%) in the large papillary tumors. Hence, mice treated with DASO2/VC had decreased frequencies of Kras2 mutations and reduced numbers of small and large papillary tumors, suggesting that activation of the Kras2 gene may be implicated in lung tumor formation and progression.

Focusing on the pervasive role of microRNAs (miRNAs), we review the multiple steps of malignant transformation, outlining the common hallmarks of tumorigenesis: self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis. For each of these traits, we provide examples of miRNA contribution to the acquisition of a malignant phenotype. Finally, through an overview of the remarkable ability of miRNAs to regulate entire pathwaysas a result of the multiplicity of their targets, we highlight the attractive potential of developing miRNAtargeted therapies, which should affect all the aspects of tumorigenesis.

T acute lymphoblastic leukemia cell lines treated with hexamethylene bisacetamide (HMBA) undergo a delay in cell cycle progression and increase susceptibility to apoptosis, although they never overcome the differentiation block. In accordance with changes in cell cycle and apoptosis, transitory p53 pathway activation commonly occurs. Bcl-2 inhibition further favours the pro-apoptotic effect of HMBA. Notch1 expression is down regulated by reduction of its transcription level. Accordingly, Notch1 protein and transcriptional activity were affected. Even if HMBA generally reduces Notch1 level in T acute lymphoblastic leukemia (T-ALL) cell lines, this does not commonly influence the biological response; in fact all the analysed cell lines, except CEM cells, display no biological effect following DAPT-induced Notch inhibition.

Cancer is a collection of complex genetic diseases characterized by multiple defects in the homeostatic mechanisms that regulate cell growth, proliferation and differentiation. Although the analysis of human tumor specimens has allowed the identification of many molecules and pathways important for the malignant phenotype, we still lack a complete understanding of the events that conspire to program any specific type of cancer. Recent advances in developing human experimental models of cancer have provided new insights into the pathways whose perturbation is necessary to achieve cell transformation. These studies indicate that many combinations of genetic mutations confer tumorigenicity on human cells and that both cell-type and tumor-stromal interactions play critical roles in dictating the tumor phenotype.

Lung cancer has become the most common cause of cancer-related mortality in the world in both men and women. Despite the development of aggressive protocols utilizing chemotherapy, radiation therapy, and surgery, the overall survival of lung cancer has changed little, with less than 15% of patients surviving longer than 5 years. Because of these poor results and the recognition that cancer is caused by molecular defects, research has focused on developing novel therapeutics to try to correct these underlying genetic defects and reverse the malignant phenotype. The development of viral vectors (adenoviral and retroviral) has allowed this strategy to be carried out in the clinic because these vectors have allowed genes to be transferred into tumors at high levels of efficiency and expression. This paper focuses on preliminary results from clinical studies utilizing p53 gene therapy strategies in lung cancer to determine the therapeutic potential of this novel therapy and to try to identify subsets of patients who could potentially benefit from this treatment.

This study was designed to determine the clinical implication of expression of progesterone receptor form A (PR-A) and B (PR-B) mRNAs in secondary spreading of gynecologic cancers. Approximately equal expression of PR-A and PR-B mRNAs was designated as type AB and dominant expression of PR-B mRNA as type B. Alteration from type AB to type B in the metastatic cancers occurred in 3 8 cases of uterine endometrial cancers, 2 8 cases of uterine cervical cancers, and 2 8 cases of ovarian cancers. Other cancers revealed type B regardless of primary or metastatic status. thus, all metastatic cancers studied revealed type B. These results suggest that transcription of PR-A mRNA may be damaged, which might lead to uncontrolled overexpression of PR-B mRNA in metastatic lesion, and that the type B status could reveal a highly malignant phenotype in these three gynecologic cancers.

The Ras-Raf-MAPK pathway has been implicated in lung carcinogenesis and, potentially, the maintenance of the malignant phenotype in these tumors. Mutations in ras and B-raf genes have been described in lung cancer, representing one of the few examples of tandem mutations in a signaling cascade. As a result, numerous approaches to inhibiting this pathway in lung cancer have been explored in the past decade. The most promising approach to date appears to be the inhibition of mitogen-activated ERK kinase or MEK. In this review, the potential utility of MEK inhibitors in the therapy of lung cancer is discussed.

During the last decade remarkable progress has been made in our understanding of the malignant phenotype. There is evidence that a series of genetic changes are involved in the conversion of a normal cell to a malignant one. These changes have been directly identified with mutations in various genes usually involved in cell growth and proliferation. Two main classes of genes have been characterized: oncogenes, which promote growth and tumor suppressor genes, which restrain growth. While oncogenes have been studied in relative detail, little is known about tumor suppressor genes. However recent studies revealed that loss of tumor suppressor genes are a common mechanism for the progression of cancer and are of prognostic value. In this review we focus on the role of these tumor suppressor genes in urologic tumors in experimental as well as clinical studies.

A surprising finding in the report by Rahman et al. in this issue of Cancer Cell is that forced overexpression of human thymidylate synthase transforms immortalized murine cells into a malignant phenotype. We discuss the possibility that elevated levels of thymidylate synthase noted in some human malignancies may contribute to tumor progression and may also reflect increased levels of its transcriptional activator E2F-1.