"The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway." (Source: MeSH)
Figure: An overview of major signal transduction pathways
Source: https://en.wikipedia.org/wiki/File:Signal_transduction_pathways.svg (License: CC BY-SA 3.0)
Introduction to Cancer Biology (Part 1): Abnormal Signal Transduction
mechanismsinmedicine.com Educational animation which explains the mechanism of abnormal signal transduction resulting in uncontrolled cell proliferation. This animation also provides an overview of the potential targets of anticancer therapies.
This list of publications is regularly updated (Source: PubMed).
Andrikopoulou M, Salakos N, Deligeoroglou E, et al. The role of mTOR signaling pathway in premalignant and malignant cervical lesions. Eur J Gynaecol Oncol. 2015; 36(1):36-43 [PubMed] Related Publications
PURPOSE OF THE STUDY: Aberrant activation of the Akt/mTOR/pS6 signaling pathway has been identified in various types of cancer and is under investigation in cervical cancer. The purpose of this study was to assess the expression of the phosphorylated/activated forms of Akt (upstream molecule), 4E-BP1 and pS6 (downstream molecules) in biopsy samples of cervical low grade squamous intraepithelial lesions (LSIL), high grade squamous intraepithelial lesions (HSIL), and squamous cell carcinoma (Ca) compared to normal cervical epithelium. MATERIAL AND METHODS: The study included 38 cases diagnosed as LSIL, 31 cases as HSIL, 29 cases as Ca, and eight control cases from normal cervix. Immunohistochemistry was used to assess the expression of pAkt, p4E-BP1 and pS6. RESULTS: Statistical analysis revealed significant differences between HSIL and Ca groups compared to controls regarding intensity, positivity, and total scores for all three molecules (p < 0.001). A trend for higher expression with increasing grade of dysplasia was demonstrated. CONCLUSION: These results strongly support the view that the mTOR signaling pathway is involved in cervical carcinogenesis.
Zhang L, Zhou Y, Cheng C, et al. Genomic analyses reveal mutational signatures and frequently altered genes in esophageal squamous cell carcinoma. Am J Hum Genet. 2015; 96(4):597-611 [PubMed] Article available free on PMC after 02/10/2015 Related Publications
Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide and the fourth most lethal cancer in China. However, although genomic studies have identified some mutations associated with ESCC, we know little of the mutational processes responsible. To identify genome-wide mutational signatures, we performed either whole-genome sequencing (WGS) or whole-exome sequencing (WES) on 104 ESCC individuals and combined our data with those of 88 previously reported samples. An APOBEC-mediated mutational signature in 47% of 192 tumors suggests that APOBEC-catalyzed deamination provides a source of DNA damage in ESCC. Moreover, PIK3CA hotspot mutations (c.1624G>A [p.Glu542Lys] and c.1633G>A [p.Glu545Lys]) were enriched in APOBEC-signature tumors, and no smoking-associated signature was observed in ESCC. In the samples analyzed by WGS, we identified focal (<100 kb) amplifications of CBX4 and CBX8. In our combined cohort, we identified frequent inactivating mutations in AJUBA, ZNF750, and PTCH1 and the chromatin-remodeling genes CREBBP and BAP1, in addition to known mutations. Functional analyses suggest roles for several genes (CBX4, CBX8, AJUBA, and ZNF750) in ESCC. Notably, high activity of hedgehog signaling and the PI3K pathway in approximately 60% of 104 ESCC tumors indicates that therapies targeting these pathways might be particularly promising strategies for ESCC. Collectively, our data provide comprehensive insights into the mutational signatures of ESCC and identify markers for early diagnosis and potential therapeutic targets.
Immune checkpoint therapy, which targets regulatory pathways in T cells to enhance antitumor immune responses, has led to important clinical advances and provided a new weapon against cancer. This therapy has elicited durable clinical responses and, in a fraction of patients, long-term remissions where patients exhibit no clinical signs of cancer for many years. The way forward for this class of novel agents lies in our ability to understand human immune responses in the tumor microenvironment. This will provide valuable information regarding the dynamic nature of the immune response and regulation of additional pathways that will need to be targeted through combination therapies to provide survival benefit for greater numbers of patients.
Das S, Martinez LR, Ray S Phospholipid remodeling and eicosanoid signaling in colon cancer cells. Indian J Biochem Biophys. 2014; 51(6):512-9 [PubMed] Article available free on PMC after 02/10/2015 Related Publications
Phospholipid remodeling and eicosanoid synthesis are central to lipid-based inflammatory reactions. Studies have revealed that membrane phospholipid remodeling by fatty acids through deacylation/reacylation reactions increases the risk of colorectal cancers (CRC) by allowing the cells to produce excess inflammatory eicosanoids, such as prostaglandins, thromboxanes and leukotrienes. Over the years, efforts have been made to understand the lipid remodeling pathways and to design anti-cancer drugs targeting the enzymes of eicosanoid biosynthesis. Here, we discuss the recent progress in phospholipid remodeling and eicosanoid biosynthesis in CRC.
Ray A, Alalem M, Ray BK Insulin signaling network in cancer. Indian J Biochem Biophys. 2014; 51(6):493-8 [PubMed] Related Publications
The primary function of insulin is viewed as a hormone that controls blood glucose level. However, there is growing evidence that aberrant insulin level and insulin-mediated signaling can lead to cancer development and progression. The insulin-cancer relationship has stemmed from various observational and epidemiological studies, which linked higher incidence of cancer with central obesity, type II diabetes and other conditions associated with increased levels of circulating insulin, insulin resistance and hyperinsulinemic states. Increased risk of developing a range of cancers is also seen with a certain treatment options used to lower blood glucose level in diabetic patients. While metformin monotherapy has the lowest risk of developing cancer, in comparison, treatment with insulin or insulin secretagogues shows more likelihood to develop solid cancers. Cellular signaling initiated by insulin provides a clue regarding these diverse cellular outcomes. This review discusses how the insulin enacts such diverse physiological effects and the insulin-cancer relationship, with focus on the role of insulin signaling in cancer.
Martinez-Outschoorn UE, Sotgia F, Lisanti MP Caveolae and signalling in cancer. Nat Rev Cancer. 2015; 15(4):225-37 [PubMed] Related Publications
It has been over 20 years since the discovery that caveolar lipid rafts function as signalling organelles. Lipid rafts create plasma membrane heterogeneity, and caveolae are the most extensively studied subset of lipid rafts. A newly emerging paradigm is that changes in caveolae also generate tumour metabolic heterogeneity. Altered caveolae create a catabolic tumour microenvironment, which supports oxidative mitochondrial metabolism in cancer cells and which contributes to dismal survival rates for cancer patients. In this Review, we discuss the role of caveolae in tumour progression, with a special emphasis on their metabolic and cell signalling effects, and their capacity to transform the tumour microenvironment.
Graziani G, Artuso S, De Luca A, et al. A new water soluble MAPK activator exerts antitumor activity in melanoma cells resistant to the BRAF inhibitor vemurafenib. Biochem Pharmacol. 2015; 95(1):16-27 [PubMed] Related Publications
Recovery of mitogen activated protein kinase (MAPK) or activation of alternative pathways, such as the PI3K/AKT/mTOR, are involved in acquired resistance to BRAF inhibitors which represent the first-line treatment of BRAF-mutated metastatic melanoma. We recently demonstrated that 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (NBDHEX) and its water soluble analog 2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)ethoxy)ethoxy)ethanol (MC3181) trigger apoptosis in BRAF V600E mutated melanoma cells through activation of the MAPK c-Jun N-terminal kinase (JNK). Herein, we investigated whether NBDHEX and MC3181 might exert antitumor activity against BRAF V600E mutated human melanoma cells rendered resistant to the BRAF inhibitor vemurafenib. To this aim we generated a subline of A375 melanoma resistant in vitro and in vivo to vemurafenib (A375-VR8) and characterized by NRAS G13R mutation, high basal levels of CRAF protein and phospho-activation of AKT. In these cells ERK phosphorylation was not significantly down-modulated by vemurafenib concentrations capable of abrogating ERK phosphorylation in sensitive A375 cells. Both NBDHEX and MC3181 induced marked antiproliferative and apoptotic effects in A375-VR8 cells and, at equitoxic concentrations, caused a strong phosphorylation of JNK, p38, and of the downstream mediators of apoptosis ATF2 and p53. Drug treatment further increased ERK phosphorylation, which was required for the cellular response to the NBD derivatives, as apoptosis was antagonized by the ERK inhibitor FR180204. Finally, in vivo administration of MC3181 provoked JNK activation at the tumor site and markedly reduced A375-VR8 growth. These evidences strongly suggest that the activation of multiple pro-apoptotic MAPK pathways by MC3181 might represent a new strategy for the treatment of melanoma resistant to BRAF inhibitors.
Jiang L, Zhang C, Wu Y, et al. 67kDa laminin receptor regulates the activation of MAPKs through DUSPs in glioma cell line U251. J BUON. 2015 Jan-Feb; 20(1):253-60 [PubMed] Related Publications
PURPOSE: All-trans-retinoic-acid (ATRA), the active derivative of vitamin A, is critical in regulating cell cycle as well as inhibiting tumor growth and angiogenesis. It has been used in the clinical treatment of leukemia. 67kDa laminin receptor (67LR), as one of the receptor of laminin, plays an important role in tumor cells invasion, proliferation and metastasis. Current research indicates that 67LR is highly expressed in glioma and is associated with tumor progression. However, the underlying molecular mechanisms, especially the signaling pathways involved, have not been reported yet. Therefore it is of great importance to clarify its downstream targets. METHODS: The U251 glioma cell line was used in this study. Cell Counting Kit-8 was used in cell proliferation assay. Quantitative real-time PCR (qRT-PCR) was used to determine the transcription level of dual specificity phosphatases (DUSPs). Western blot analysis was used to detect the expression of mitogen activated protein kinases (MAPKs) and phosphorylated MAPKs. RESULTS: 67LR could influence the transcription of DUSPs and expression of MAPKs. ATRA could enhance the expression of 67LR in U251 cells and this enhancement was dose-dependent. ATRA was able to inhibit the growth of U251 cells. CONCLUSIONS: ATRA expressed significant therapeutic effect on glioma cells, and 67LR is not the only factor that can influence the proliferation of U251 cells.
Zhang CZ, Wang XD, Wang HW, et al. Sorafenib inhibits liver cancer growth by decreasing mTOR, AKT, and PI3K expression. J BUON. 2015 Jan-Feb; 20(1):218-22 [PubMed] Related Publications
PURPOSE: The purpose of this study was to determine the impact of sorafenib on PI3K/AKT/mTOR signaling pathway and to further define its mechanism for treating hepatocellular carcinoma (HCC). METHODS: Human SMMC-7721 hepatic carcinoma cells were treated with or without 4 μmoL/L sorafenib. SMMC- 7721 cells were harvested at various time points (0-48 hrs) and assessed for changes in PI3K, mTOR, and AKT protein and mRNA levels. RESULTS: Human SMMC-7721 hepatic tumor cells exposed to sorafenib had decreased expression of PI3K/mTOR/AKT. CONCLUSION: Sorafenib appears to inhibit hepatic tumor growth by downregulating PI3k/Akt/mTOR signaling pathway.
Hara Y, Yamashita T, Oishi N, et al. TSU-68 ameliorates hepatocellular carcinoma growth by inhibiting microenvironmental platelet-derived growth factor signaling. Anticancer Res. 2015; 35(3):1423-31 [PubMed] Related Publications
BACKGROUND: TSU-68 is a multikinase inhibitor that targets platelet-derived growth factor receptors (PDGFRs). In the present study, we evaluated the effect of TSU-68 on the tumor-microenvironment interaction in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: HCC and fibroblast cell lines (HuH7, Hep3B, HuH1 and WI-38) were used to evaluate their interactions. Cancer characteristics were evaluated by spheroid formation and tumorigenicity in immunodeficient mice. Time-lapse image analysis was performed to monitor cell motility. RESULTS: Although PDGFA was abundantly expressed, PDGFR-α was predominantly located in the cytoplasm and was not functional in HuH7 cells. Co-culture experiments demonstrated that HCC cells induced phosphorylation of PDGFR-α in WI-38 fibroblasts and that stimulated fibroblasts, in turn, boosted the spheroid formation capacity of HCC cells. TSU-68 inhibited phosphorylation of PDGFR-α in WI-38 cells and suppressed the growth of subcutaneously co-injected HuH7/WI-38 tumor xenografts. CONCLUSION: TSU-68 inhibits stromal PDGF signaling activated by cancer cells and suppresses HCC growth.
Zuo M, Rashid A, Churi C, et al. Novel therapeutic strategy targeting the Hedgehog signalling and mTOR pathways in biliary tract cancer. Br J Cancer. 2015; 112(6):1042-51 [PubMed] Article available free on PMC after 17/03/2016 Related Publications
BACKGROUND: Activation of the PI3K/mTOR and Hedgehog (Hh) signalling pathways occurs frequently in biliary tract cancer (BTC). Crosstalk between these pathways occurs in other gastrointestinal cancers. The respective signalling inhibitors rapamycin and vismodegib may inhibit BTC synergistically and suppress cancer stem cells (CSCs). METHODS: Gene expression profiling for p70S6k and Gli1 was performed with BTC cell lines. Tumour and pathway inhibitory effects of rapamycin and vismodegib were investigated in BTC preclinical models and CSCs. RESULTS: Rapamycin and vismodegib synergistically reduced BTC cell viability and proliferation. This drug combination arrested BTC Mz-ChA-1 cells in the G1 phase but had no significant effect on the cell cycle of BTC Sk-ChA-1 cells. Combined treatment inhibited the proliferation of CSCs and ALDH-positive cells. Nanog and Oct-4 expression in CSCs was decreased by the combination treatment. Western blotting results showed the p-p70S6K, p-Gli1, p-mTOR, and p-AKT protein expression were inhibited by the combination treatment in BTC cells. In an Mz-ChA-1 xenograft model, combination treatment resulted in 80% inhibition of tumour growth and prolonged tumour doubling time. In 4 of 10 human BTC specimens, tumour p-p70S6K and Gli1 protein expression levels were decreased with the combination treatment. CONCLUSIONS: Targeted inhibition of the PI3K/mTOR and Hhpathways indicates a new avenue for BTC treatment with combination therapy.
Sun SS, Zhang L, Yang J, Zhou X Role of runt-related transcription factor 2 in signal network of tumors as an inter-mediator. Cancer Lett. 2015; 361(1):1-7 [PubMed] Related Publications
Runt-related transcription factor 2 (RUNX2) is a member of the polyomavirus enhancer-binding protein 2/core-binding factor superfamily. RUNX2 is known for its contribution to osteoblast phenotype and bone formation. In recent years, increasing attention has been focused on the relationship of Runx2 with tumorigenesis. In different types of tumor cells, RUNX2 cooperates with its co-activators or co-inhibitors, and mediates the responses of cells to various signaling pathways that are hyperactive in tumors. Thus, several downstream target genes of RUNX2 are activated when RUNX2 interacts with its co-factors, leading to a variety of effects on tumor cells (epithelial-mesenchymal transition, metastasis, proliferation, and osteolytic lesion). This review focuses on the involvement of RUNX2 in tumor cells in the crosstalk of diverse signaling pathways and its multiple functions to develop optimal and feasible approaches for clinical treatment based on the functions of RUNX2.
Montero J, Sarosiek KA, DeAngelo JD, et al. Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy. Cell. 2015; 160(5):977-89 [PubMed] Article available free on PMC after 26/02/2016 Related Publications
There is a lack of effective predictive biomarkers to precisely assign optimal therapy to cancer patients. While most efforts are directed at inferring drug response phenotype based on genotype, there is very focused and useful phenotypic information to be gained from directly perturbing the patient's living cancer cell with the drug(s) in question. To satisfy this unmet need, we developed the Dynamic BH3 Profiling technique to measure early changes in net pro-apoptotic signaling at the mitochondrion ("priming") induced by chemotherapeutic agents in cancer cells, not requiring prolonged ex vivo culture. We find in cell line and clinical experiments that early drug-induced death signaling measured by Dynamic BH3 Profiling predicts chemotherapy response across many cancer types and many agents, including combinations of chemotherapies. We propose that Dynamic BH3 Profiling can be used as a broadly applicable predictive biomarker to predict cytotoxic response of cancers to chemotherapeutics in vivo.
Oshimori N, Oristian D, Fuchs E TGF-β promotes heterogeneity and drug resistance in squamous cell carcinoma. Cell. 2015; 160(5):963-76 [PubMed] Related Publications
Subsets of long-lived, tumor-initiating stem cells often escape cancer therapies. However, sources and mechanisms that generate tumor heterogeneity and drug-resistant cell population are still unfolding. Here, we devise a functional reporter system to lineage trace and/or genetic ablate signaling in TGF-β-activated squamous cell carcinoma stem cells (SCC-SCs). Dissecting TGF-β's impact on malignant progression, we demonstrate that TGF-β concentrating near tumor-vasculature generates heterogeneity in TGF-β signaling at tumor-stroma interface and bestows slower-cycling properties to neighboring SCC-SCs. While non-responding progenies proliferate faster and accelerate tumor growth, TGF-β-responding progenies invade, aberrantly differentiate, and affect gene expression. Intriguingly, TGF-β-responding SCC-SCs show increased protection against anti-cancer drugs, but slower-cycling alone does not confer survival. Rather, TGF-β transcriptionally activates p21, which stabilizes NRF2, thereby markedly enhancing glutathione metabolism and diminishing effectiveness of anti-cancer therapeutics. Together, these findings establish a surprising non-genetic paradigm for TGF-β signaling in fueling heterogeneity in SCC-SCs, tumor characteristics, and drug resistance.
Lee JC, Chung LC, Chen YJ, et al. Upregulation of B-cell translocation gene 2 by epigallocatechin-3-gallate via p38 and ERK signaling blocks cell proliferation in human oral squamous cell carcinoma cells. Cancer Lett. 2015; 360(2):310-8 [PubMed] Related Publications
Oral squamous cell carcinoma (OSCC) is a well-known malignancy that accounts for the majority of oral cancers. B-cell translocation gene 2 (BTG2) is an important regulator of cell cycle dynamics in cancer cells. However, the role of BTG2 in OSCC cells and the influences of epigallocatechin-3-gallate (EGCG) on BTG2 gene expressions have not been well evaluated. The objectives of this study were to examine the effect of EGCG-induced BTG2 expression and the potential signal pathways involved. The (3)H-thymidine incorporation and Western-blot assays revealed cell proliferation was attenuated by EGCG via upregulation of BTG2 expression causing cell cycle G1 phase arrest in OSCC cells. BTG2 overexpression decreased tumor cell growth, while BTG2 knockdown illuminated the opposite effect in xenograft animal studies. Overexpressed BTG2 arrested the cell cycle at the G1 phase and downregulated protein expressions of cyclin A, cyclin D, and cyclin E. Western-blot assays indicated that EGCG induced phosphorylation of p38, JNK, and ERK. However, pretreatments with selective mitogen-activated protein kinase (MAPK) inhibitors, SB203580 (p38 inhibitor) and PD0325901 (ERK1/2 inhibitor), significantly suppressed the activation of EGCG on BTG2 expression. Our results indicate that EGCG attenuates cell proliferation of OSCC cells by upregulating BTG2 expression via p38 and ERK pathways.
Xing C, Zhang R, Cui J, et al. Pathway crosstalk analysis of non-small cell lung cancer based on microarray gene expression profiling. Tumori. 2015 Jan-Feb; 101(1):111-6 [PubMed] Related Publications
AIMS AND BACKGROUND: Lung cancer is characterized by uncontrolled cell growth in the lung tissue. A major challenge in cancer research is the biological interpretation of the complexity of cancer somatic mutation profiles. This study examines the role of pathway crosstalk in the metastatic process of lung cancer cells based on DNA microarray analysis. METHODS: We downloaded the gene expression profile GSE10096 from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified and the gene functions of selected DEGs were further analyzed. After KEGG pathway analysis, dysfunctional pathways and dysfunctional crosstalk between pathways in two types of lung cancer cells (low metastasis, M1, and high metastasis, M5) were examined. RESULTS: A total of 13433 genes were filtered as DEGs, and after pathway analysis, 108 signaling pathways related to cancer signaling pathways were screened, including a host pathway hsa05223 and 79 neighbor pathways. Dysfunctional crosstalk analysis of pathways revealed that pathway crosstalk dysfunction of M1 and M5 cells mainly occurred between hsa05223 (non-small cell lung cancer) and hsa04310 (Wnt signaling pathway), and between non-small cell lung cancer and hsa04520 (adherens junction), respectively. Significant pathway crosstalk dysfunction also existed between adherens junction and other classical signaling pathways such as hsa04110 (cell cycle), hsa04310 (Wnt signaling pathway), hsa04350 (TGF-beta signaling pathway), and hsa04630 (Jak-STAT signaling pathway). CONCLUSIONS: Our discovery will help to elucidate the molecular mechanisms of the high carcinogenic and metastatic potential of lung cancer cells. In addition, it will pave the way to developing effective therapies for lung cancer.
Virshup DM Moving upstream in the war on WNTs. J Clin Invest. 2015; 125(3):975-7 [PubMed] Article available free on PMC after 02/03/2016 Related Publications
Cholangiocarcinoma is a relatively rare cancer of the biliary ducts that is highly refractory to treatment. The factors that drive cholangiocarcinoma are poorly understood, though chronic liver fluke infection is a risk factor for disease. In this issue of the JCI, Boulter and colleagues demonstrate that the WNT/β-catenin signaling pathway is upregulated in patients with sporadic cholangiocarcinoma. The authors determined that macrophages generate WNT ligands in cholangiocarcinomas and depletion or inhibition of this cell population in animal models of cholangiocarcinoma reduced tumor burden and proliferation. Moreover, pharmacological inhibition of WNT secretion or β-catenin activity was efficacious in animal models. Together the results of this study suggest that targeting WNT has potential as a therapeutic strategy for cholangiocarcinoma.
Boulter L, Guest RV, Kendall TJ, et al. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited. J Clin Invest. 2015; 125(3):1269-85 [PubMed] Article available free on PMC after 02/03/2016 Related Publications
Cholangiocarcinoma (CC) is typically diagnosed at an advanced stage and is refractory to surgical intervention and chemotherapy. Despite a global increase in the incidence of CC, little progress has been made toward the development of treatments for this cancer. Here we utilized human tissue; CC cell xenografts; a p53-deficient transgenic mouse model; and a non-transgenic, chemically induced rat model of CC that accurately reflects both the inflammatory and regenerative background associated with human CC pathology. Using these systems, we determined that the WNT pathway is highly activated in CCs and that inflammatory macrophages are required to establish this WNT-high state in vivo. Moreover, depletion of macrophages or inhibition of WNT signaling with one of two small molecule WNT inhibitors in mouse and rat CC models markedly reduced CC proliferation and increased apoptosis, resulting in tumor regression. Together, these results demonstrate that enhanced WNT signaling is a characteristic of CC and suggest that targeting WNT signaling pathways has potential as a therapeutic strategy for CC.
Pusceddu S, de Braud F, Concas L, et al. Rationale and protocol of the MetNET-1 trial, a prospective, single center, phase II study to evaluate the activity and safety of everolimus in combination with octreotide LAR and metformin in patients with advanced pancreatic neuroendocrine tumors. Tumori. 2014 Nov-Dec; 100(6):e286-9 [PubMed] Related Publications
Abnormal PI3K-AKT-mTOR pathway signalling and autocrine activation of the mTOR pathway, mediated through insulin-like growth factor-1, have been implicated in the proliferation of pancreatic neuroendocrine tumor (pNET) cells. Everolimus, an mTOR inhibitor, has shown antitumor benefit in pNETs alone and in combination with octreotide LAR in RADIANT-1 and RADIANT-3 studies. Although everolimus-based phase II/III trials have improved progression-free survival for pNET, its use has not impacted on prolonging overall survival. Metformin has recently shown some anti-cancer activity in both in vitro and in vivo studies by its indirect properties to decrease insulin and insulin-like growth factor-1 (IGF-1) levels and by its antitumour effect to promote AMPK activation and consequently inhibition to TSC1-2/mTOR complex. In light of even more retrospective evidence of metformin's anticancer activity, a prospective evaluation is required to either confirm or discard these preliminary findings. With the aim to evaluate the antiproliferative effect of metformin in combination with everolimus and octreotide LAR in pancreatic well-differentiated neuroendocrine tumor patients, a single arm, prospective, single center phase II study was designed (MetNET-1 trial, NCT 02294006). Forty-three patients are expected to be evaluated. The study is ongoing, and recruitment is estimated to be completed in August 2016. The results will be anticipated in 2017.
Oshima H, Nakayama M, Han TS, et al. Suppressing TGFβ signaling in regenerating epithelia in an inflammatory microenvironment is sufficient to cause invasive intestinal cancer. Cancer Res. 2015; 75(4):766-76 [PubMed] Related Publications
Genetic alterations in the TGFβ signaling pathway in combination with oncogenic alterations lead to cancer development in the intestines. However, the mechanisms of TGFβ signaling suppression in malignant progression of intestinal tumors have not yet been fully understood. We have examined Apc(Δ716) Tgfbr2(ΔIEC) compound mutant mice that carry mutations in Apc and Tgfbr2 genes in the intestinal epithelial cells. We found inflammatory microenvironment only in the invasive intestinal adenocarcinomas but not in noninvasive benign polyps of the same mice. We thus treated simple Tgfbr2(ΔIEC) mice with dextran sodium sulfate (DSS) that causes ulcerative colitis. Importantly, these Tgfbr2(ΔIEC) mice developed invasive colon cancer associated with chronic inflammation. We also found that TGFβ signaling is suppressed in human colitis-associated colon cancer cells. In the mouse invasive tumors, macrophages infiltrated and expressed MT1-MMP, causing MMP2 activation. These results suggest that inflammatory microenvironment contributes to submucosal invasion of TGFβ signaling-repressed epithelial cells through activation of MMP2. We further found that regeneration was impaired in Tgfbr2(ΔIEC) mice for intestinal mucosa damaged by DSS treatment or X-ray irradiation, resulting in the expansion of undifferentiated epithelial cell population. Moreover, organoids of intestinal epithelial cells cultured from irradiated Tgfbr2(ΔIEC) mice formed "long crypts" in Matrigel, suggesting acquisition of an invasive phenotype into the extracellular matrix. These results, taken together, indicate that a simple genetic alteration in the TGFβ signaling pathway in the inflamed and regenerating intestinal mucosa can cause invasive intestinal tumors. Such a mechanism may play a role in the colon carcinogenesis associated with inflammatory bowel disease in humans.
Changchien JJ, Chen YJ, Huang CH, et al. Quinacrine induces apoptosis in human leukemia K562 cells via p38 MAPK-elicited BCL2 down-regulation and suppression of ERK/c-Jun-mediated BCL2L1 expression. Toxicol Appl Pharmacol. 2015; 284(1):33-41 [PubMed] Related Publications
Although previous studies have revealed the anti-cancer activity of quinacrine, its effect on leukemia is not clearly resolved. We sought to explore the cytotoxic effect and mechanism of quinacrine action in human leukemia K562 cells. Quinacrine induced K562 cell apoptosis accompanied with ROS generation, mitochondrial depolarization, and down-regulation of BCL2L1 and BCL2. Upon exposure to quinacrine, ROS-mediated p38 MAPK activation and ERK inactivation were observed in K562 cells. Quinacrine-induced cell death and mitochondrial depolarization were suppressed by the p38MAPK inhibitor SB202190 and constitutively active MEK1 over-expression. Activation of p38 MAPK was shown to promote BCL2 degradation. Further, ERK inactivation suppressed c-Jun-mediated transcriptional expression of BCL2L1. Over-expression of BCL2L1 and BCL2 attenuated quinacrine-evoked mitochondrial depolarization and rescued the viability of quinacrine-treated cells. Taken together, our data indicate that quinacrine-induced K562 cell apoptosis is mediated through mitochondrial alterations triggered by p38 MAPK-mediated BCL2 down-regulation and suppression of ERK/c-Jun-mediated BCL2L1 expression.
Guo G, Gao F CXCR3: latest evidence for the involvement of chemokine signaling in bone cancer pain. Exp Neurol. 2015; 265:176-9 [PubMed] Related Publications
Growing evidence indicates that chemokines participate in the generation and maintenance of bone cancer pain (BCP). Recent work in Exp Neurol by Guan et al. (2015) demonstrated the involvement of spinal chemokine receptor CXCR3 and its downstream PI3K/Akt and Raf/MEK/ERK signaling pathways in BCP. This work provides new evidence to support that chemokines participate in central sensitization in BCP condition. Reviewed evidence suggests that few chemokines have been proved to be related to cancer pain. The underlying relationship between CXCR3 signaling and BCP condition requires further study.
Abdel-Rahman O Hedgehog pathway aberrations and gastric cancer; evaluation of prognostic impact and exploration of therapeutic potentials. Tumour Biol. 2015; 36(3):1367-74 [PubMed] Related Publications
Gastric cancer is an important cause for mortality and morbidity worldwide; it lies in the fourt rank as a cause of cancer-related death in males and in the fifth rank of cancer-related death in women. The prognosis of advanced/metastatic gastric cancer cases looks poor with the majority of available therapeutics. Thus, novel therapeutic strategies in this setting have been considered a priority for leading cooperative oncology groups. Hedgehog(Hh) pathway aberrations have sparked particular interest as prognostic markers with data from multiple studies showing consistent evidence of a poor prognostic value of Gli over expression in gastric cancer while on the other hand the prognostic significance of Hh protein over expression (particularly SHH) was not consistent among different studies. This review article revises the prognostic and potential therapeutic opportunities in the targeting of hedgehog pathway in gastric cancer.
Abetov D, Mustapova Z, Saliev T, Bulanin D Biomarkers and signaling pathways of colorectal cancer stem cells. Tumour Biol. 2015; 36(3):1339-53 [PubMed] Related Publications
The progression of colorectal cancer is commonly characterized by accumulation of genetic or epigenetic abnormalities, altering regulation of gene expression as well as normal protein structures and functions. Nonetheless, there are some questions that remain to be elucidated, such as the origin of cancer cells and populations of cells initiating and propagating tumor development. Currently, there are two rival theories describing the process of carcinogenesis. One is the stochastic model, arguing that any cell is capable of initiating and triggering the development of cancer. Meanwhile, the cancer stem cell model hypothesizes that only a small fraction of stem cells possesses cancer-promoting properties. Typically, colorectal cancer stem cells (CSCs) share the same molecular signaling profiles with normal stem cells or embryonic stem cells, such as Wnt, Notch, TGF-β, and Hedgehog. Nevertheless, CSCs differ from normal stem cells and the bulk of tumor cells in their tumorigenic potential and susceptibility to chemotherapeutic drugs. This may be a possible explanation of the high percentage of cancer recurrence in patients who underwent chemotherapeutic treatment and surgery. This review article focuses on the colorectal cancer stem cell biomarkers and the role of upregulated signaling pathways implicated in the initiation and progression of colorectal cancer.
Mallinger A, Crumpler S, Pichowicz M, et al. Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen. J Med Chem. 2015; 58(4):1717-35 [PubMed] Related Publications
WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine-piperidine bond of 9 by small-molecule X-ray crystallography. Medicinal chemistry optimization to maintain this twisted conformation, cognisant of physicochemical properties likely to maintain good cell permeability, led to 74 (CCT251545), a potent small-molecule inhibitor of WNT signaling with good oral pharmacokinetics. We demonstrate inhibition of WNT pathway activity in a solid human tumor xenograft model with evidence for tumor growth inhibition following oral dosing. This work provides a successful example of hypothesis-driven medicinal chemistry optimization from a singleton hit against a cell-based pathway assay without knowledge of the biochemical target.
Mabuchi S, Kuroda H, Takahashi R, Sasano T The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer. Gynecol Oncol. 2015; 137(1):173-9 [PubMed] Related Publications
The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway plays a critical role in the malignant transformation of human tumors and their subsequent growth, proliferation, and metastasis. Preclinical investigations have suggested that the PI3K/AKT/mTOR pathway is frequently activated in ovarian cancer, especially in clear cell carcinoma and endometrioid adenocarcinoma. Thus, this pathway is regarded as an attractive candidate for therapeutic interventions, and inhibitors targeting different components of this pathway are in various stages of clinical development. Here, we highlight the recent progress that has been made in our understanding of the PI3K/AKT/mTOR pathway and discuss the potential of therapeutic agents that target this pathway as treatments for ovarian cancer and the obstacles to their development.
Ji BC, Hsiao YP, Tsai CH, et al. Cantharidin impairs cell migration and invasion of A375.S2 human melanoma cells by suppressing MMP-2 and -9 through PI3K/NF-κB signaling pathways. Anticancer Res. 2015; 35(2):729-38 [PubMed] Related Publications
Cancer metastasis is the major cause of cancer patient death. Melanoma is a highly important metastasis in human cancer. Cantharidin (CTD), identified as an active component of natural mylabris (Mylabris phalerata Pallas), induces apoptosis in many human cancer cells. In the present study, we investigated the anti-metastasis effects of CTD in human melanoma cancer A375.S2 cells. Flow cytometry was used to measure CTD-induced cytotoxic effects in A375.S2 cells. Wound healing assay indicated that CTD suppressed the migration of A375.S2 cells in a dose-dependent manner. The Matrigel Transwell Assay was used for cell migration and invasion examination and the results showed that CTD inhibited both. Gelatin zymography was used to investigate the activities of MMP-2/9 and the results indicated that CTD inhibited the enzymatic activities of MMP-2/9 in A375.S2 cells. The protein expression of A375.S2 cells following incubation with CTD was examined by western blotting and the results showed that CTD decreased the expression of ERK1/2, PI3K, FAK, MMP-2, -9, COX-2, NF-κB p65, TIMP 1, TIMP 2, VEFG, uPA, Rho A, GRB2, ROCK-1 and Ras, but increased the expressions of p38, JNK, p-c-jun and PKC. Based on those observations, we suggest that CTD may be used as a novel anti-cancer metastasis agent of human melanoma cancer in the future.
Kwasnicki A, Jeevan D, Braun A, et al. Involvement of mTOR signaling pathways in regulating growth and dissemination of metastatic brain tumors via EMT. Anticancer Res. 2015; 35(2):689-96 [PubMed] Related Publications
BACKGROUND: Metastatic dissemination to the brain may involve a process termed epithelial-mesenchymal transition (EMT), which results in a migratory, invasive and proliferative cell phenotype. Recent studies suggest that Mechanistic target of rapamycin (mTOR, that exists in two multi-protein complexes (mTORC1 and mTORC2), may regulate EMT, in addition to controlling cell growth, survival, metabolism and motility. However, the role of mTOR in brain metastases remains elusive. We hypothesize that mTOR plays a crucial role in the process of EMT in brain metastasis and therefore serves as a target of therapy. MATERIALS AND METHODS: Immunohistochemical analyses were performed to determine the expression of components of mTOR pathways. Immunofluorescence and immunoblotting were executed to determine the markers of EMT after treatments with siRNA or inhibitors of mTOR pathways. Cell proliferation using MTT, S-phase entry by determining EdU-incorporation, chemotactic and scratch-wound migration assays were performed. RESULTS: Metastatic tumor samples expressed components of mTOR pathways, namely, mTOR, Raptor and Rictor with a significant overlap. Metastatic potential was enhanced in an astrocytic environment and suppressed following mTOR inhibition. mTOR inhibition resulted in nuclear localization of the epithelial marker of EMT, E-cadherin, and enhancement in expression of the mesenchymal marker vimentin. CONCLUSION: Results suggest that the mTOR pathway is activated in metastatic brain tumors, and inhibition of mTOR signaling could provide therapeutic value in the management of patients with brain metastases.
Mok MT, Cheng AS CUL4B: a novel epigenetic driver in Wnt/β-catenin-dependent hepatocarcinogenesis. J Pathol. 2015; 236(1):1-4 [PubMed] Related Publications
Emerging evidence indicates that Cullin 4B (CUL4B), a major component of ubiquitin ligase complexes, is over-expressed in diverse cancer types with pro-tumourigenic effects. In this issue of the Journal of Pathology, Yuan and colleagues  elucidated the oncogenic activity of CUL4B in hepatocellular carcinoma (HCC) and delineated its role in driving Wnt/β-catenin signalling. In addition to the stabilization of β-catenin protein against proteasomal degradation, CUL4B also acts in concert with enhancer of Zeste homologue 2 (EZH2) to concordantly silence multiple Wnt inhibitors. These findings provide significant mechanistic insights into the epigenetic activation of the Wnt/β-catenin pathway in HCC and shed light on the functional importance of ubiquitination in this intricate regulatory system.
Li G, Shan C, Liu L, et al. Tanshinone IIA inhibits HIF-1α and VEGF expression in breast cancer cells via mTOR/p70S6K/RPS6/4E-BP1 signaling pathway. PLoS One. 2015; 10(2):e0117440 [PubMed] Article available free on PMC after 02/03/2016 Related Publications
Hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) play important roles in angiogenesis and tumor growth. Tanshinone IIA (T2A) is a novel antiangiogenic agent with promising antitumor effects; however, the molecular mechanism underlying the antiangiogenic effects of T2A remains unclear. In the present study, we provided evidence showing that T2A inhibited angiogenesis and breast cancer growth by down-regulating VEGF expression. Specifically, T2A repressed HIF-1α expression at the translational level and inhibited the transcriptional activity of HIF-1α, which led to the down-regulation of VEGF expression. Suppression of HIF-1α synthesis by T2A correlated with strong dephosphorylation of mammalian target of rapamycin (mTOR) and its effectors ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), a pathway regulating HIF-1α expression at the translational level. In addition, we also found that T2A inhibited the angiogenesis and growth of human breast cancer xenografts in nude mice through suppression of HIF-1α and VEGF. Our study provides novel perspectives and potential targets for the treatment of human breast cancer.