Fundamental Role In Tumorigenesis Research Articles

Long Non-Coding RNAs as Regulators for Targeting Breast Cancer Stem Cells and Tumor Immune Microenvironment: Biological Properties and Therapeutic Potential.

Breast cancer stem cells (BCSCs) is a subpopulation of cancer cells with self-renewal and differentiation capacity, have been suggested to give rise to tumor heterogeneity and biologically aggressive behavior. Accumulating evidence has shown that BCSCs play a fundamental role in tumorigenesis, progression, and recurrence. The development of immunotherapy, primarily represented by programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors, has greatly changed the treatment landscape of multiple malignancies. Recent studies have identified pervasive negative associations between cancer stemness and anticancer immunity. Stemness seems to play a causative role in the formation of cold tumor immune microenvironment (TIME). The multiple functions of long non-coding RNAs (lncRNAs) in regulating stemness and immune responses has been recently highlighted in breast cancer. The review focus on lncRNAs and keys pathways involved in the regulation of BCSCs and TIME. Potential clinical applications using lncRNAs as biomarkers or therapies will be discussed.

Abstract 4758: SETD4 transcription levels correlates with leukemic burden and SMYD2 transcription in acute lymphoblastic leukemia

Abstract Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy worldwide. It has a history of great rates of success in treatment, but adults and infants still share a dismal prognosis. This condition makes the development of new prognostic markers linked to effective therapeutic strategies a matter of pressing concern. While cancer has traditionally been viewed as a genetic disease derived from alterations in oncogenes and tumor suppressors, it is well known nowadays that epigenetic changes also play a fundamental role in tumorigenesis. The SET family of lysine methyltransferases (KMT) has been implicated in a number of cancers, and SETD4 is a member that is still poorly characterized. In the present study we used qPCR to analyze the expression pattern of SETD4 among 83 pediatric ALL patients and non-neoplastic bone marrow (BM) samples and investigated the correlation between SETD4 transcription changes with the leukemic burden in ALL patients during chemotherapy. We found that SETD4 transcription levels are significantly upregulated in BM samples derived from ALL patients compared to non-neoplastic BM (8,5-fold higher, p < 0,001) and its expression correlated with leukemic burden. Importantly, levels of SETD4 decreased in patients that responded to chemotherapy treatment. We further investigated whether SETD4 transcription levels associates with that of SMYD2, another KMT previously identified as a prognostic marker in ALL. Transcription levels of SETD4 and SMYD2 were examined on day 15th and 29th of chemotherapy. Surprisingly, a high level of correlation (Spearman r = 0.925, p < 0.01) between both genes was observed in both treatment time points. Finally, survival outcomes were worst in ALL patients with high levels of SETD4 transcription (log-rank test, p < 0,05), evidencing its dysregulated expression is associated with an unfavorable disease prognosis. Together, these results point to SETD4 as a useful prognostic marker, a possible tool to assess response to therapy and an attractive target for drug development. Citation Format: Luis Augusto Muniz Telles, Luis Henrique Sakamoto, Alan Jhones Assis, Doralina de Amaral Rabello, Andrea Barretto Motoyama, Fabio Pittella-Silva. SETD4 transcription levels correlates with leukemic burden and SMYD2 transcription in acute lymphoblastic leukemia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4758.

Sensitive Interrogation of Enhancer Activity in Living Cells on a Nanoelectroporation-Probing Platform.

Enhancers involved in the upregulation of multiple oncogenes play a fundamental role in tumorigenesis and immortalization. Exploring the activity of enhancers in living cells has emerged as a critical path to a deep understanding of cancer properties, further providing important clues to targeted therapy. However, identifying enhancer activity in living cells is challenging due to the double biological barriers of a cell cytoplasmic membrane and a nuclear membrane, limiting the sensitivity and responsiveness of conventional probing methods. In this work, we developed a nanoelectroporation-probing (NP) platform, which enables intranuclear probe delivery for sensitive interrogation of enhancer activity in living cells. The nanoelectroporation biochip achieved highly focused perforation of the cell cytoplasmic membrane and brought about additional driving force to expedite the delivery of probes into the nucleus. The probes targeting enhancer activity (named "PH probe") are programmed with a cyclic amplification strategy and enable an increase in the fluorescence signals over 100-fold within 1 h. The platform was leveraged to detect the activity of CCAT1 enhancers (CCAT1, colon cancer-associated transcript-1, a long noncoding RNA that functions in tumor invasion and metastasis) in cell samples from clinical lung cancer patients, as well as reveal the heterogeneity of enhancers among different patients. The observations may extend the linkages between enhancers and cancer cells while validating the robustness and reliability of the platform for the assay of enhancer activity. This platform will be a promising toolbox with wide applicable potential for the intranuclear study of living cells.

MicroRNA and cancer: a focus on mammary tumors in female dogs

ABSTRACT: Mammary tumors are the most frequent tumors reported in female dogs and have great relevance in veterinary oncology; however, little is known about the molecular mechanisms involved in the development of metastasis. An increasing number of human studies have suggested that epigenetic alterations, such as DNA methylation, miRNA, and histone modifications, are the predominant events leading to the metastatic phenotype in tumor cells and participate in regulating oncogenic signals associated with tumor spread. Among these epigenetic alterations, miRNAs have stood out in recent years, presenting a fundamental role in tumorigenesis. There are still few studies evaluating the role of miRNAs in canine mammary tissues. Thus, this paper aims to review the role of miRNAs in cancer with a special focus on canine mammary tumors.

Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells

Deregulated signal transduction and energy metabolism are hallmarks of cancer and both play a fundamental role in tumorigenesis. While it is increasingly recognised that signalling and metabolism are highly interconnected, the underpinning mechanisms of their co-regulation are still largely unknown. Here we designed and acquired proteomics, phosphoproteomics, and metabolomics experiments in fumarate hydratase (FH) deficient cells and developed a computational modelling approach to identify putative regulatory phosphorylation-sites of metabolic enzymes. We identified previously reported functionally relevant phosphosites and potentially novel regulatory residues in enzymes of the central carbon metabolism. In particular, we showed that pyruvate dehydrogenase (PDHA1) enzymatic activity is inhibited by increased phosphorylation in FH-deficient cells, restricting carbon entry from glucose to the tricarboxylic acid cycle. Moreover, we confirmed PDHA1 phosphorylation in human FH-deficient tumours. Our work provides a novel approach to investigate how post-translational modifications of enzymes regulate metabolism and could have important implications for understanding the metabolic transformation of FH-deficient cancers with potential clinical applications.

Molecular Pathways: The Balance between Cancer and the Immune System Challenges the Therapeutic Specificity of Targeting Nuclear Factor-κB Signaling for Cancer Treatment.

The NF-κB signaling pathway is a complex network linking extracellular stimuli to cell survival and proliferation. Cytoplasmic signaling to activate NF-κB can occur as part of the DNA damage response or in response to a large variety of activators, including viruses, inflammation, and cell death. NF-κB transcription factors play a fundamental role in tumorigenesis and are implicated in the origination and propagation of both hematologic and solid tumor types, including melanoma, breast, prostate, ovarian, pancreatic, colon, lung, and thyroid cancers. On the other hand, NF-κB signaling is key to immune function and is likely necessary for antitumor immunity. This presents a dilemma when designing therapeutic approaches to target NF-κB. There is growing interest in identifying novel modulators to inhibit NF-κB activity as impeding different steps of the NF-κB pathway has potential to slow tumor growth, progression, and resistance to chemotherapy. Despite significant advances in our understanding of this pathway, our ability to effectively clinically block key targets for cancer therapy remains limited due to on-target effects in normal tissues. Tumor specificity is critical to developing therapeutic strategies targeting this antiapoptotic signaling pathway to maintain antitumor immune surveillance when applying such therapy to patients. Clin Cancer Res; 22(17); 4302-8. ©2016 AACR.

Abstract 2023: SOX4 is essential for PTEN-mediated prostate tumorigenesis in vivo

Abstract Prostate cancer is the most common cancer and the second leading cause of cancer mortality in American men, underscoring the significance of unraveling the molecular mechanisms involved in the initiation and progression of the disease. The sex-determining region Y-box 4 (SOX4) gene is overexpressed in many types of human cancers, including prostate cancer, suggesting that SOX4 plays a fundamental role in tumorigenesis. In this study, we demonstrate that SOX4 is critical for PTEN-mediated prostate cancer progression in vivo. We show that homozygous deletion of Sox4 in the adult prostate epithelium strongly inhibits tumor progression initiated by homozygous loss of the Pten tumor suppressor, demonstrating the key role of SOX4 in the development of prostate cancer. Homozygous deletion of Sox4 also reduces the activation of AKT and β-catenin in Pten-null mice, resulting in inhibition of an invasive cancer phenotype. We also show that SOX4 expression is induced by loss of PTEN, and that PI3K-AKT-mTOR signaling activity is critical for SOX4 expression, suggesting a positive feedback loop between SOX4 protein and PI3K-AKT-mTOR activity. Our findings indicate that SOX4 is a critical component of the PTEN-PI3K-AKT pathway in prostate cancer, suggesting that SOX4 may be a promising molecular target for novel combinatorial therapies for both primary and advanced prostate cancers. Citation Format: Birdal Bilir, Adeboye O. Osunkoya, W. Guy Wiles, Soma Sannigrahi, Veronique Lefebvre, Daniel Metzger, Demetri D. Spyropoulos, W. David Martin, Carlos S. Moreno. SOX4 is essential for PTEN-mediated prostate tumorigenesis in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2023.

Abstract 4323: ALK overexpression is associated with activation of PI3K/AKT signaling pathway in PTC

Abstract Aberrant activation of anaplastic lymphoma kinase (ALK) gene caused by mutation, rearrangement or overexpression plays a fundamental role in tumorigenesis in several tumors and represents an important therapeutic target. Currently, only limited data is available on thyroid cancer with respect to the genetic alteration of ALK. Therefore we investigate the ALK overexpression and amplification, and its correlation with various clinicopathological features and molecular biomarkers in a large cohort of 1040 Middle Eastern PTC. In our study, ALK protein expression was determined by immunohistochemistry. ALK gene amplification and rearrangement were analyzed by in situ hybridization (FISH). We also correlated the data with clinicopathological characteristics and other molecular markers. Our data showed that ALK is overexpressed in 136 of the 997 (13.6%) PTC samples. ALK amplification and rearrangement were not observed by FISH. ALK overexpression was significantly associated with surgical margin, but had no effect on the survival of PTC patients. Interestingly, ALK overexpression was found to be significantly correlated with the higher expression of pAKT and PIK3CA in PTC samples, suggesting that ALK overexpression is associated with activation of PI3K/AKT signaling pathway in PTC. In addition, ALK overexpression is also correlated with overexpression of anti-apopototic marker XIAP and BCL-XL and cell cycle regulatory marker SKP2. Altogether, our results suggest that ALK overexpression presents in a small subset of samples and is not associated with survival in PTC. However ALK overexpression is significantly correlated with PI3K/AKT signaling pathway and might provide a potential therapeutic target for PTC patients with ALK overexpression. Citation Format: Rong Bu, Sarita Prabhakaran, Shaham Beg, Zeenath Jehan, Abdul K. Siraj, Maqbool Ahmed, Azhar Hussain, Saif A. Alsobhi, Fouad Al-Dayel, Shahab Uddin, Khawla S. Al-Kuraya. ALK overexpression is associated with activation of PI3K/AKT signaling pathway in PTC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4323. doi:10.1158/1538-7445.AM2015-4323

Abstract C132: Targeting heat shock factor 1 improves the antitumor efficiency of hyperthermia.

Abstract The heat-shock response is a powerful transcriptional program which acts genome-wide, not only to restore normal protein folding through the induction of heat shock proteins (HSP), but to re-shape global cellular pathways controlling survival, growth and metabolism. In mammals, this response is regulated primarily by the Heat Shock Factor 1 (HSF1) transcription factor. We have previously shown that HSF1 plays a fundamental role in tumorigenesis, by promoting the survival and malignance of tumor cells, both in tissue culture and in mouse models of cancer [1]. HSF1 exerts its role by activating a unique transcriptional program in the cancer cells [2]. Indeed, increased HSF1 levels, as well as activation of its transcriptional signature, are associated with reduced survival in breast, lung and colon cancer patients [3]. Cancer cells are exquisitely dependent on HSF1 for survival. Exposure to additional stress, such as heat, further increases their dependency on HSF1. Recently we described how translation is linked to HSF1 activation using a derivative of the natural compound rocaglamide [4]. We found that this drug-like inhibitor of translation-initiation inhibits HSF1 and leads to tumor regression in hematopoietic malignancies. Here we combine this compound, or genetic inhibition of HSF1 expression, with focal heat therapy delivered via gold nano rods. We find that inhibiting HSF1 in solid tumors increases the efficiency of hyperthermia as an anticancer treatment. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C132. Citation Format: Ruth Scherz-Shouval, Alexander F. Bagley, Luke Whitesell, Sangeeta N. Bhatia, Susan Lindquist. Targeting heat shock factor 1 improves the antitumor efficiency of hyperthermia. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C132.

Challenges in the clinical development of PI3K inhibitors

The PI3K/Akt/mTOR pathway is one of the most frequently dysregulated signaling pathways in cancer and an important target for drug development. PI3K signaling plays a fundamental role in tumorigenesis, governing cell proliferation, survival, motility, and angiogenesis. Activation of the pathway is frequently observed in a variety of tumor types and can occur through several mechanisms. These mechanisms include (but are not limited to) upregulated signaling via the aberrant activation of receptors upstream of PI3K, amplification or gain-of-function mutations in the PIK3CA gene encoding the p110α catalytic subunit of PI3K, and inactivation of PTEN through mutation, deletion, or epigenetic silencing. PI3K pathway activation may occur as part of primary tumorigenesis, or as an adaptive response (via molecular alterations or increased phosphorylation of pathway components) that may lead to resistance to anticancer therapies. A range of PI3K inhibitors are being investigated for the treatment of different types of cancer; broad clinical development plans require a flexible yet well-structured approach to clinical trial design.

Abstract A23: Cell autonomous and nonautonomous activities of heat shock factor 1 support tumor initiation, progression, and metastasis

Abstract The heat-shock response is a powerful transcriptional program which acts genome-wide, not only to restore the normal protein folding through the induction of heat shock proteins (HSP), but to re-shape global cellular pathways controlling survival, growth and metabolism. In mammals, this response is regulated primarily by the Heat Shock Factor 1 (HSF1) transcription factor. We have previously shown that HSF1 plays a fundamental role in tumorigenesis, by promoting the survival and malignance of tumor cells, both in tissue culture and in mouse models of cancer [1]. Recently we demonstrated that HSF1 exerts its role by activating a unique transcriptional program in the cancer cells, that is distinct from the one activated during heat shock [2]. In breast cancer and several other types of carcinoma, we found that high HSF1 protein levels and activation of the HSF1-dependent transcriptional program are associated with poor clinical outcome [3]. Here we show that HSF1 is activated not only in the tumor cells, but also in the stromal cells infiltrating the tumor. Examining human patient samples, we find immunohistochemical evidence for activation of HSF1 in the stroma. Using mouse xenograft models and in vitro co-culture we show that HSF1 in the stroma supports tumor cell growth. Finally, expression profiling and analysis of the DNA binding pattern of HSF1 in tumors and in cell culture indicates that stromal HSF1 supports tumorigenesis by activating a unique, stroma-specific transcriptional program. Taken together, our data suggests that HSF1 acts in the cancer cells and in the stroma to activate distinct, yet complimentary transcriptional programs that will facilitate tumor initiation, progression and metastasis.

Abstract 1151: microRNAs affect therapeutic sensitivity of human gliobastoma to temozolomide

Abstract Glioma is among the most deadly type of cancer. In spite of the enormous improvements made the prognosis of malignant glioma has remained poor over the last decade. Many glial-derived tumors seem to be particularly resistant to apoptosis following DNA damage. MicroRNAs (miRNA) represent a novel class of small RNAs that might play a fundamental role in tumorigenesis, cell proliferation, migration and apoptosis. Temozolomide is an alkylating agent used in glioma patients that alkylates/methylates DNA. The alkylation damages the DNA and triggers the death of tumor cells. O6-methylguanine DNA methyltransferase (MGMT) is a DNA repair enzyme which removes DNA adducts. MGMT activity is frequently lost in glioblastoma in the presence of CpG island hypermethylation in the promoter region. The methylation status of the MGMT promoter is considered to be indicative of a good outcome in patients with malignant gliomas. However, in some studies the correlation between MGMT promoter methylation and MGMT expression levels are contradictory. Other possible mechanisms of MGMT modulation should exist. Therefore, we investigated the role of miRs on the regulation of MGMT expression levels. We analyzed temozolomide sensitivity of human glioma cell lines, T98G and U87MG. T98G resulted resistant to temozolomide, whereas U87MG cells were sensitive. Through a microarray analysis we provided evidences that miR-221/222 are differentially expressed in U87MG compared to T98G cells. Bioinformatics analysis through RNA Hybrid indicated a possible match between MGMT 3’UTR and miR-221/222. Luciferase assay confirmed that miR-221/222 are capable to bind the 3’UTR of MGMT and to impair its mRNA translation. Western blot and RT-PCR analysis upon synthetic pre-miR-221/222 transfection of T98G cells indicated that MGMT levels were significantly decreased. At the contrar, the transfection of U87MG cells with anti-miR-221/222 induced an increase of MGMT levels. Therefore this data indicate that MGMT is a new target of miRs -221/222. The analysis of cell death with MTT, Annexin V and colony assay upon temozolomide treatment in cells whose miR-221/222 levels were modulated, demonstrated an important role of those miRs in temozolomide sensitivity. All these data indicate that miR-221/222 might represent a new strategy for regulation of MGMT expression levels and thus temozolomide sensitivity and an improvement in chemotherapy strategy for glioblastoma patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1151. doi:10.1158/1538-7445.AM2011-1151

Genetic Alterations in the Phosphatidylinositol-3 Kinase/Akt Pathway in Thyroid Cancer

Aberrant activation of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway plays a fundamental role in thyroid tumorigenesis, particularly in follicular thyroid cancer (FTC) and aggressive thyroid cancer, such as anaplastic thyroid cancer (ATC). As the drivers of this process, many genetic alterations activating the PI3K/Akt pathway have been identified in thyroid cancer in recent years. This review summarizes the current knowledge on major genetic alterations in the PI3K/Akt pathway. These include PIK3CA mutations and genomic amplification/copy gain, Ras mutations, PTEN mutations, RET/PTC and PPARgamma/Pax8 rearrangements, as well as amplification/copy gain of PIK3CB, PDK1, Akt, and various receptor tyrosine kinase genes. Most of these genetic alterations are particularly common in FTC and many of them are even more common in ATC; they are generally less common in papillary thyroid cancer (PTC), in which the MAP kinase (MAPK) pathway activated by the BRAF mutation instead plays a major role. Methylation and, thus, epigenetic silencing of PTEN, a major negative regulator of the PI3K/Akt pathway, occurs in close association with activating genetic alterations of the PI3K/Akt pathway, constituting a unique self-enhancement mechanism for this pathway. Many of these genetic alterations are mutually exclusive in differentiated thyroid tumors, but with increasing concurrence from benign tumors to FTC to ATC. RET/PTC, Ras, and receptor tyrosine kinase could dually activate the PI3K/Akt and MAPK pathways. Most cases of ATC harbor genetic alterations in these genes or other genetic combinations that can activate both pathways. It is proposed that genetic alterations in the PI3K/Akt pathway promote thyroid cell transformation to FTC and that genetic alterations in the MAPK pathway promote cell transformation to PTC; accumulation of multiple genetic alterations that can activate both pathways promotes thyroid cancer aggressiveness and progression to ATC. Genetic alterations are common in the PI3K/Akt pathway in thyroid cancer and play a fundamental role in the tumorigenesis and progression of this cancer. This provides a strong basis for the emerging development of novel genetic-based diagnostic, prognostic, and therapeutic strategies for thyroid cancer.

Abstract LB-351: miR-221&222 regulate cell motility in glioma cell lines targeting the protein phosphates PTPμ

Abstract Glioblastoma multiforme (GBM) is the most frequent brain tumor in adults and is the most lethal form of human cancer. Despite the improvements in treatments, patients's survival remains poor. Different evidences indicate that microRNAs might play a fundamental role in tumorigenesis, cell proliferation, migration and apoptosis. Through a microarray analysis we identified different microRNAs upregulated in the tumorigenic glioma cell lines U87 compared with the non tumorigenic cell lines T98G. Among different microRNAs we focused our attention on miR221&222. By bioinformatic analysis we identified a binding site for these two miRs in the 3′UTR of the protein phosphatase PTPμ. Luciferase assay confirmed that miR-221 and 222 bind to the 3′UTR of PTPμ and impairs its mRNA translation. Previous studies indicated that PTPμ suppresses cell migration/invasion and is downregulated in glioma. Significantly, we found that miR 221&222 overexpression induced a downregulation of PTPμ as analyzed by both western blot and RT-PCR. Furthermore, miR222&221 induced an increase in cell migration/invasion in glioma cells. Accordingly, we found an inverse correlation between miR221&222 and PTPμ in glioma cancer samples, as analyzed by immunohistochemistry and in situ hybridization on a tissue array representing 46 glioma and normal brain tissues. In conclusion, our results suggest that microRNA 221&222 might regulate glioma tumorigenesis through the control of cell migration process. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-351.

ING4 Mediates Crosstalk between Histone H3 K4 Trimethylation and H3 Acetylation to Attenuate Cellular Transformation

Aberrations in chromatin dynamics play a fundamental role in tumorigenesis, yet relatively little is known of the molecular mechanisms linking histone lysine methylation to neoplastic disease. ING4 (Inhibitor of Growth 4) is a native subunit of an HBO1 histone acetyltransferase (HAT) complex and a tumor suppressor protein. Here we show a critical role for specific recognition of histone H3 trimethylated at lysine 4 (H3K4me3) by the ING4 PHD finger in mediating ING4 gene expression and tumor suppressor functions. The interaction between ING4 and H3K4me3 augments HBO1 acetylation activity on H3 tails and drives H3 acetylation at ING4 target promoters. Further, ING4 facilitates apoptosis in response to genotoxic stress and inhibits anchorage-independent cell growth, and these functions depend on ING4 interactions with H3K4me3. Together, our results demonstrate a mechanism for brokering crosstalk between H3K4 methylation and H3 acetylation and reveal a molecular link between chromatin modulation and tumor suppressor mechanisms.

MicroRNA-21 Knockdown Disrupts Glioma Growth In vivo and Displays Synergistic Cytotoxicity with Neural Precursor Cell–Delivered S-TRAIL in Human Gliomas

Despite the development of new glioma therapies that allow for tumor-targeted in situ delivery of cytotoxic drugs, tumor resistance to apoptosis remains a key impediment to effective treatment. Mounting evidence indicates that microRNAs (miRNA) might play a fundamental role in tumorigenesis, controlling cell proliferation and apoptosis. In gliomas, microRNA-21 (miR-21) levels have been reported to be elevated and their knockdown is associated with increased apoptotic activity. We hypothesized that suppression of miR-21 might sensitize gliomas for cytotoxic tumor therapy. With the use of locked nucleic acid (LNA)-antimiR-21 oligonucleotides, bimodal imaging vectors, and neural precursor cells (NPC) expressing a secretable variant of the cytotoxic agent tumor necrosis factor-related apoptosis inducing ligand (S-TRAIL), we show that the combined suppression of miR-21 and NPC-S-TRAIL leads to a synergistic increase in caspase activity and significantly decreased cell viability in human glioma cells in vitro. This phenomenon persists in vivo, as we observed complete eradication of LNA-antimiR-21-treated gliomas subjected to the presence of NPC-S-TRAIL in the murine brain. Our results reveal the efficacy of miR-21 antagonism in murine glioma models and implicate miR-21 as a target for therapeutic intervention. Furthermore, our findings provide the basis for developing combination therapies using miRNA modulation and cytotoxic tumor therapies.

Cyclin E in normal and neoplastic cell cycles

Cyclin E-Cdk2 has long been considered an essential and master regulator of progression through G1 phase of the cell cycle. Although recent mouse models have prompted a rethinking of cyclin E function in mammals, it remains clear that cyclin E impacts upon many processes central to cell division. Normal cells maintain strict control of cyclin E activity, and this is commonly disrupted in cancer cells. Moreover, cyclin E deregulation is thought to play a fundamental role in tumorigenesis. In this review, we discuss the regulation and functions of cyclin E in normal and neoplastic mammalian cells.

Développement des inhibiteurs de farnésyl transférase comme agents anticancéreux

Ras proteins belong to the monomeric GTPases familly. They control cell growth, differentiation, proliferation, and survival. Ras mutations are frequently found in human cancers and play a fundamental role in tumorigenesis. Ras requires localization to the plasma membrane to exert its oncogenic effects. This subcelllular localization is dependent of protein farnesylation which is a post translational modification catalysed by the farnesyl transferase enzyme. Farnesyl transferase Inhibitors (FTI) were then designed ten to twelve years ago to inhibit ras processing and consequently the growth of ras mutated tumor. Preclinical data show that FTIs inhibit cell proliferation and survival in vitro and in vivo of a wide range of cancer cell lines, many of which contain wild type ras suggesting that mutated Ras is not the only target of the FTIs effects. Four FTIs went then through clinical trials and three of then are still developed in the clinic. Phase I et II clinical trials confirmed a relevant antitumor activity and a low toxicity. Phase III clinical trials are currently undergoing for both solid and hematologic tumors. The expected results should allow to define the position of FTIs as anticancer drugs, particularly in combination with conventional chemotherapy, hormone therapy, radiotherapy or any other new targeted compound.

Apoptosis in the human female reproductive tract.

Throughout fetal and adult life, the balance of cell proliferation and cell death determines the size of cell populations in tissues throughout the body. Apoptosis, or programmed cell death, is the physiologic process of cell deletion. Cell death is critical in morphogenesis in the embryo and fetus as well as in maintaining tissue homeostasis in the adult. Throughout the menstrual cycle, cell death and renewal occur in the female reproductive tract in a highly regulated sequence. The process of follicular atresia and the cyclic shedding of the endometrium involve the process of apoptosis. In pathologic states, resistance to cell death by apoptosis may play a fundamental role in tumorigenesis. Because apoptosis is such a fundamental biologic process in a variety of physiologic and pathologic states, many unique to the female reproductive tract, it is imperative that clinicians be conversant with the rapidly expanding information in this area. Although apoptotic cell death has been recognized histologically for over 20 years (1), the molecular mechanisms that regulate apoptosis have only recently begun to be elucidated. The identification of some of these regulators, such as the p53 gene, has improved our understanding of the mechanisms of tumor response to chemotherapy. This review will summarize our current knowledge of the mechanisms of apoptosis in the ovary and endometrium, and in the normal development and malignant transformation of the breast.