Category Archives: Research

New Signal Model may help elucidate the Occurrence Mechanism of Tumor Vessels

Researchers from Rice University have developed a new model which may assist elucidate that how tumor manipulate vessels growth to receive benefits. This study was published in PNAS.

Angiogenesis, the formation of new blood vessels from existing ones, is a vital process during embryonic development, homeostasis, and tumor progression. This process starts when cells release angiogenic growth factors such as VEGF in response to hypoxia.

New Signal Model may help elucidate the Occurrence Mechanism of Tumor Vessels

The selection of the tip and the stalk cell fate is critical for developing a functional vessel. This decision is mediated by Notch signaling pathway (2), an evolutionarily conserved cell–cell communication pathway involved in cell fate decisions in multiple contexts. This pathway is activated when Notch (transmembrane receptor) belonging to a particular cell interacts with Delta or Jagged (transmembrane ligands) belonging to its neighboring cell (trans-activation), thereby releasing the Notch intracellular domain (NICD).

Developing effective antiangiogenesis strategies remains clinically challenging. Unlike physiological angiogenesis, pathological angiogenesis comprises of many microvessels that do not fully mature or develop functionally, because the cell fate decision about which endothelial cells become the tip and lead the following stalk cells is dysregulated.

In this study, scientists devised a specific theoretical framework to decipher the cross-talk between two crucial players of the decision-making process of tip and stalk cell fate: VEGF and Notch-Delta-Jagged signaling. They find that high expression of Jagged, but not Delta, can destabilize the terminal differentiation into tip or stalk cells and give rise to a hybrid tip/stalk phenotype, a phenotype that can transform physiological into pathological angiogenesis.

 

Their results offer insights into why tumor-stroma communication often implicates Jagged.

Inhibitors of PI3K found to Promote Cancer Metastasis

Researchers from The Wistar Institute have identified that sole use of inhibitors of PI3K in the cancer therapy may promote the metastasis to cause deterioration. This study was published in PNAS.

Inhibitors of PI3K found to Promote Cancer Metastasis

The phosphatidylinositol 3-kinase (PI3K) is a universal tumor driver that integrates growth factor signaling with downstream circuitries of cell proliferation, metabolism, and survival. Exploited in nearly every human tumor, including through acquisition of activating mutations, PI3K signaling is an important therapeutic target and several small-molecule antagonists of this pathway have entered clinical testing.

Despite the promise of personalized cancer medicine, most molecular therapies produce only modest and short-lived patient gains. In addition to drug resistance, it is also possible that tumors adaptively reprogram their signaling pathways to evade therapy-induced “stress” and, in the process, acquire more aggressive disease traits.

In this study, scientists show that small-molecule inhibitors of PI3K, a cancer node and important therapeutic target, induce transcriptional and signaling reprogramming in tumors. This involves the trafficking of energetically active mitochondria to subcellular sites of cell motility, where they provide a potent, “regional” energy source to support tumor cell invasion. Although this response may paradoxically increase the risk of metastasis during PI3K therapy, targeting mitochondrial reprogramming is feasible, and could provide a novel therapeutic strategy.

Scientists Found tRNAs may Promote Cancer Cell Growth

Scientists from US have identified that hormone-related breast cancer and prostate cancer could specifically produce one kind of small RNAs which are originated from tRNAs. They play a very important role in promoting cell growth. This study was published in PNAS.

Scientists Found tRNAs may Promote Cancer Cell Growth

Transfer RNAs (tRNAs) are universally expressed in all three domains of life, and play a central role in protein synthesis as an adapter molecule translating codon triplet sequences into amino acids. Mature tRNAs are 70- to 90- nucleotides (nt) non-coding RNA molecules forming a cloverleaf secondary structure that further folds into a L-shaped tertiary structure. The human nuclear genome encodes over 500 tRNA genes over 500 tRNA genes, along with numerous genes of tRNA-lookalikes resembling nuclear and mitochondrial tRNAs.

Although transfer RNAs(tRNAs) are best known as adapter molecules essential for translation, recent biomedical and computational evidence has led to a previously unexpected conceptual consensus that tRNAs are not always end products but can further serve as a source of small functional RNAs, termed SHOT-RNAs, are specifically and abundantly expressed in sex hormone-dependent breast and prostate cancers. SHOT-RNAs are produced from aminoacylated mature tRNAs by angiogenin-mediated cleavage of the anticodon loop, which is promoted by sex hormones and their receptors.

In this study, researchers identified the complete repertoire of SHOT-RNAs, and also found their functional significance in cell proliferation. These results have unveiled a novel tRNA-engaged pathway in tumorigenesis.

 

Break Cell Energy Station, Open “Tumor Mode”

Researchers from University of Pennsylvania have found that the defect of mitochondria play a very important role in the transition from normal cells to cancer cells. This study was published in Oncogene.

Break Cell Energy Station, Open “Tumor Mode”

In keeping with the Warburg hypothesis proposing aerobic glycolysis as an important factor in tumor growth, altered mitochondrial function and increased utilization of glucose for energy are hallmarks of many proliferation tumors. A number of studies have shown defective mitochondrial electron transport chain complexes (ETC) in human cancers.

Loss of mtDNA copy number has been reported in breast, prostate, hepatocellular and lung cancers. In this study, researchers have shown that partial mtDNA depletion mediates tumorigenesis by activating a Ca2+-Calcineurin (Cn)-dependent retrograde signaling. The onset of this signaling is characterized by loss of mitochondrial membrane potential.

In this study, scientists show that silencing of subunits IVi1 or Vb of CcO induces a mitochondrial retrograde signaling, which largely mimics the signaling that they reported in mtDNA-depleted cells. The cells acquired invasiveness and showed loss of contact inhibition generally observed in tumor cells. There was increased expression of marker genes of the Ca2+/Cn signaling pathway.

As expected, these cells with disrupted CcO complex showed many features of ‘Warburg Effect,’ including increased dependence on glycolysis and invasive behavior in otherwise non-tumorigenic C2C12 skeletal myoblasts. Similarly, in cell lines derived from esophageal and breast cancers, loss of cytochrome oxidase increased invasiveness. Strikingly, in C2C12 cells, these changes were reversed by reconstituting subunit IVi1-silenced cells with wild-type CcOIVi1 cDNA, thus establishing a novel role of this ETC component in the tumorigenic process.

Epigenetic silencing of Oct4 by a complex of pseudogene lncRNA

Long non-coding RNAs (lncRNAs) act as epigenetic regulators of gene expression. Oct4 is the only indispensible factor for iPS cell generation. Here we present a panel of new mouse Oct4 pseudogenes and demonstrate that the X-linked Oct4 pseudogene Oct4P4 critically impacts mouse embryonic stem cells self-renewal.

Epigenetic silencing of Oct4 by a complex of pseudogene lncRNA

We have identified four additional candidate pseudogenes that show high homology to portions of the open reading frame and untranslated regions of Oct4. Among them, Oct4P4 lncRNA forms a complex with the SUV39H1 HMTase to direct the imposition of H3K9me3 and HP1a to the promoter of the ancestral Oct4 gene, located on chromosome 17, leading to gene silencing and reduced mESC self-renewal.

Depleting Oct4P4 from differentiated pMEFs results in the re-activation of basic features of mESC pluripotency, such as self-renewal transcription factor expression. Targeting Oct4P4 expression in primary mouse embryonic fibroblasts causes the re-acquisition of self-renewing features of mESC.

In summary, we demonstrate that Oct4P4 lncRNA plays an important role in inducing and maintaining silencing of the Oct4 gene in differentiating mESCs.  The Oct4P4 lncRNA represents the first example for a crucial role of a vertebrate pseudogene derived sense lncRNAs in directing chromatin-modifying activities to the promoter of its ancestral gene.

BRD4 controls Long noncoding RNAs to regulate glioblastoma proliferation

Long non-coding RNAs (lncRNA) are non-protein coding transcripts longer than 200 nucleotides. They have been looked as rubbish of the transcripts before, however, recently study indicate that they play critical roles in cancer initiation and malignant progression. FDA has approved five epigenetic drugs for use in cancer treatment: two DNA methyltransferase (DNMT) inhibitors and three histone deacetylase (HDAC) inhibitors. BET bromodomain inhibitors exert a broad spectrum of desirable biological effects such as anticancer and anti-inflammatory properties.

BRD4 controls Long noncoding RNAs to regulate glioblastoma proliferation

Firstly, we profile lncRNAs differentially expressed in GBM. We have analyzed the RNA sequencing data by testing expression of each annotated transcript in each individual GBM sample compared against all normal samples.

Next, knockdown of HOTAIR causes apoptosis and reduces the proliferation of glioblastoma cells in vitro and in vivo.

Finally, Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumor-promoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. BRD4 bind to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression.

To summary, we have identified a mechanism that small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for GBM progression.

New Idea on Cancer Therapy

Recently, scientists from Saint Louis firstly identified that a unique target which is very different from other counterparts. It is a drug which is targeting Warburg and may block the energy source of cancer to prevent cancer cells’ growth. This study was published in Cancer Cell.

New Idea on Cancer Therapy

Metabolism in cancer cells is primarily glycolytic even when oxygen is abundant. Aerobic glycolysis or the Warburg effect is well characterized and has been shown to be driven by mitochondrial defects, oncogenic stimuli, hypoxia, and aberrantly enhanced expression of glycolytic enzymes. In particular, elevated glycolytic gene expression is pervasive in cancers of the breast, colon, prostate, and lung.

A number of small molecules that target the Warburg effect and lipgenesis have been developed but none have become clinical treatments of off-target effects such as excessive weight loss, anorexia, high toxicity, and low efficacy in vivo.

In this study, researchers describe the anti-cancer properties of an LXR inverse agonist SR9243. Unlike previously developed targeted treatments, SR9243 selectively induces apoptosis in cancer cells but spares non-malignant tissues, exhibiting significant anti-tumor activity without overt toxicity, inflammation, or weight loss. The favorable safety profile of SR9243 demonstrates that LXR inverse agonists hold significant promise as prospective clinical treatments.

Nanoparticel Carrying siRNA may Inhibit Lung Cancer Cells

Scientists from Harvard Medical School and West China School of Pharmacy have developed a unique nanoparticle platform which utilizes a kind of molecular shell made of Cationic polymer lipids and Lipid – polyethylene glycol carries siRNA as a transportation system. This study was published in PNAS.

Nanoparticel Carrying siRNA may Inhibit Lung Cancer Cells

With the capability to silence any gene of interest, RNA interference (RNAi) technology has demonstrated enormous potential in medical research and applications. RNAi-dediated gene silencing has revealed the functionality of specific genetic alterations in cancers. Many of these genes and pathways are considered “undruggable” targets or require complex and time-consuming development of effective inhibitors. The ubiquitous application of RNAi in cancer research and therapy is nevertheless hindered by the challenge of effective systemic in vivo delivery of siRNA to tumors, which requires overcoming of multiple physiological barriers, such as enzymatic mononuclear phagocyte system (MPS), and poor cellular uptake and endosomal escape.

In this study, researchers developed a new generation lipid-polymer hybrid nanoparticle platform for effective systemic delivery of small interfering RNA (siRNA) to tumors, which represents a challenging hurdle for the widespread application of RNA interference (RNAi) in cancer research and therapy. With promising in vivo features such as long blood circulation, high tumor accumulation, and effective gene silencing, the hybrid siRNA nanoparticles were successfully used to reveal and validate a putative therapeutic target. Prohibitin1 (PHB1), in non-small cell lung cancer treatment. In vivo antitumor efficacy results and human tissue microarray analysis further suggested the feasibility of utilizing PHB1 siRNA nanoparticles as a novel therapeutic agent.

This hybrid RNAi nanoparticle platform may serve as a valuable tool for validating potential cancer targets and developing new cancer therapies.

Scientists Found Fatal Weakness of Brain Cancer Stem Cells

Researchers from Washington University School of Medicine, St.Louis have discovered that even for brain cancer stem cells exist fatal weakness. Two important protein, SOX2 and CDC20, play key role in remaining the characters in brain cancer stem cells. This study was published in Cell Reports.

Scientists Found Fatal Weakness of Brain Cancer Stem Cells

Glioblastoma, the most common malignant primary tumor in adults, remain a challenging disease with a poor prognosis. Increasing appreciation of the cancer cell heterogeneity within glioblastomas has focused attention on a subpopulation of cells called tumor-initiating cells or glioblastoma stem-like cells (GSCs).

The anaphase-promoting complex (APC) E3 ubiquitin ligase functions with co-activator CDC20 to drive mitosis. CDC20-APC has been viewed as a potential strategic target in several human cancers. CDC20 mRNA is elevated in glioblastoma compared to low-grade gliomas, and CDC20 immunoreactivity in gliomas correlates with pathological grade, but little is known about the biological roles of CDC20-APC in glioblastoma.

In this study, researchers report CDC20-APC is required for GSC invasiveness and self-renewal in a manner distinct from its role in cell-cycle control. They identify pluripotency-related transcription factor SOX2 as a CDC20-interacting protein and show CDC20-APC operates through SOX2 to regulate human GSC in invasion and self-renewal. Finally, they demonstrate that CDC20-APC is essential for GSC tumorigenicity in orthotopic xenografts and that CDC20 expression has prognostic value in a subset of glioblastoma patients.

 

These results highlight a critical role for CDC20-APC in the maintenance of human GSC function, and they suggest that targeting this pathway in glioblastoma may disrupt the GSC state.

Preventing Colon Cancer by Changing Intestinal Flora

Scientists from St.Jude Children’s Hospital have identified one gene that expresses in immune system plays important role in determining the invasiveness of colon cancer. Their study was published in Cell and may play vital role in the prevention, diagnosis, and treatment of colon cancer.

Preventing Colon Cancer by Changing Intestinal Flora

Colorectal cancer is a leading cause of cancer-related deaths, with 160,000 cases being diagnosed annually in the USA. Mutations in the gene encoding AIM2 are frequently identified in patients with colorectal cancer. A previous study has shown that more than 50% of tumors from patients with small bowel cancer have frameshift mutations in the gene encoding AIM2. Further genetic evidence has shown that missense mutations are targeted to coding regions of the gene encoding AIM2 in colon cancer tissues and cell lines. AIM2 is a cytosolic double-stranded DNA receptor that contributes to the host defense against bacterial and viral pathogens.

In this study, researchers found that AIM2-deficient mice developed more tumors in the colon following azoxymethane (AOM)- and dextran sulfate sodium (DSS)-induced colitis-associated tumorigenesis. Unlike its role in the host defense against infection, AIM2 protected against tumorigenesis by controlling intestinal epithelial cell proliferation via a mechanism independent of inflammasomes and inflammatory mediators. Upon deregulated Wnt signaling, AIM2 suppressed expansion of tumor-initiating intestinal stem cells lining the base of the crypt.

Remarkbaly, reciprocal exchange of the gut microbiota between healthy WT mice and Aim2-/- mice reduced the susceptibility of Aim2-/- mice to colorectal tumorigenesis. These findings revealed a role for AIM2 and its synergy with gut microbiota in the development of colorectal cancer.