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TGF
TGF
TGFa(1) TGFb(7)

TGFα and TGFβ are upregulated in some human cancers. TGF includes two classes of growth factors: TGFα and TGFβ. These classes are not structurally or genetically related, and they act through different receptor mechanisms.(1) TGFα serves as a ligand for EGFR or as a soluble ligand. It is produced in macrophages, brain cells, and keratinocytes, and induces epithelial development. TGFβ is a cytokine with diverse effects on blood cells, and controls inflammatory responses through the regulation of chemotaxis and activation of leukocytes in the periphery, including lymphocytes, natural killer cells, dendritic cells, macrophages, mast cells, and granulocytes. Through its pleiotropic effects on these immune cells, TGFβ prevents the development of autoimmune diseases without compromising immune responses to pathogens.(2) TGFβ exists in three known subtypes in humans, TGFβ1, TGFβ2, and TGFβ3. These play crucial roles in tissue regeneration, cell differentiation, embryonic development, and regulation of the immune system. TGFβ receptors are single pass serine/threonine kinase receptors.(1)
Myostatin, encoded by the MSTN gene, is a member of the TGFβ family that inhibits muscle differentiation and growth via myogenesis. Myostatin is produced primarily in skeletal muscle cells, circulates in the blood and acts on muscle tissue, by binding a cell-bound receptor called the activin type II receptor.(3,4) Myostatin consists of two identical subunits. For it to be activated, a protease cleaves the NH2-terminal, or "pro-domain" portion of the molecule. Myostatin binds to the activin type II receptor, resulting in a recruitment of a co-receptor called Alk-3 or Alk-4. This co-receptor then initiates a cell signaling cascade in the muscle, which includes the activation of transcription factors in the SMAD family - SMAD2 and SMAD3. These factors then induce myostatin-specific gene regulation. When applied to myoblasts, myostatin inhibits their differentiation into mature muscle fibers. Myostatin has also been shown to inhibit Akt. Myostatin has been shown to directly prevent cell cycle G1 to S phase transition by decreasing levels of CDK2 and by increasing p21 levels.(5, 6)

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References

1. Adams JM CS. Bcl-2-regulated apoptosis: mechanism and therapeutic potential. Curr Opin Immunol. 2007;19(5):488-96. PMCID: 17629468.

2. Wrzesinski SH, Wan YY, Flavell RA. Transforming growth factor-? and the immune response: implications for anticancer therapy. Clinical Cancer Research. 2007;13(18):5262-70.

3. Gonzalez-Cadavid NF, Taylor WE, Yarasheski K, Sinha-Hikim I, Ma K, Ezzat S, et al. Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting. Proceedings of the National Academy of Sciences. 1998;95(25):14938-43.

4. Joulia-Ekaza D, Cabello G. The myostatin gene: physiology and pharmacological relevance. Current opinion in pharmacology. 2007;7(3):310-5.

5. McKoy G, Bicknell KA, Patel K, Brooks G. Developmental expression of myostatin in cardiomyocytes and its effect on foetal and neonatal rat cardiomyocyte proliferation. Cardiovascular research. 2007;74(2):304-12.

6. Myostatin. [cited]; Available from: http://en.wikipedia.org/wiki/Myostatin.

7. A. A. Targeting the extrinsic apoptosis pathway in cancer. Cytokine Growth Factor Rev. 2008;19:325-31. PMCID: 18495520.



News
Friday, September 16, 2016 11:13 AM|Zhong, Y., Macgregor-Das, A. M., Saunders, T., Whittle, M., Makohon-Moore, A., Kohutek, Z., Poling, J., Herbst, B., Javier, B., Cope, L., Leach, S. D., Hingorani, S. R., Iacobuzio-Donahue, C. A.|Clinical Cancer Research Online First Articles|Labels: P53, TGF, pancreatic cancer

Purpose: TP53 and the TGFβ pathway are major mediators of pancreatic cancer metastasis. The mechanisms by which they cause hematogenous metastasis have not been fully explored. Experimental Design: KPC (LSL-KRASG12D/+;LSL-Trp53R172H/+; Ptf1aCre/+) mice were generated and the frequency and morphology of organ-specific hematogenous metastases compared to that seen in KPTC and KTC littermates (Tgfbr2+/-). Key findings were validated in primary cells from each genotype and samples of human pancreatic cancer liver metastases. Results: The frequency of hematogenous metastasis in KPTC mice was significantly lower than for KPC mice (41% vs 68%, p<0.05), largely due to a reduction in liver metastases. No differences were found between KPC and KPTC lung metastases whereas liver metastases in KPTC mice showed a profound extravasation deficiency characterized by sinusoidal growth and lack of desmoplastic stroma. Analogous findings were confirmed in liver samples from patients indicating their clinical relevance. Portal vein colonization as a direct mode of access to the liver was observed in both mice and humans. Secretome analyses of KPC cells revealed an abundance of secreted prometastatic mediators including Col6A1 and Lcn2 that promoted early steps of metastatic colonization. These mediators were overexpressed in primary tumors but not metastases suggesting the ability to colonize is in part developed within the primary site, a phenomenon we refer to as the "Cinderella effect". Conclusions: These findings establish a novel paradigm for understanding pancreatic cancer metastasis and the observed clinical latencies of liver versus lung metastases specifically.

Friday, September 16, 2016 10:23 AM|Mengtao Ma, Miao He, Qian Jiang, Yuanyuan Yan, Shu Guan, Jing Zhang, Zhaojin Yu, Qiuchen Chen, Mingli Sun, Weifan Yao, Haishan Zhao, Feng Jin, Minjie Wei|International Journal of Biological Sciences|Labels: TGF, breast cancer

Tumor metastasis is a complex and multistep process and its exact molecular mechanisms remain unclear. We attempted to find novel microRNAs (miRNAs) contributing to the migration and invasion of breast cancer cells. In this study, we found that the expression of miR-487a was higher in MDA-MB-231breast cancer cells with high metastasis ability than MCF-7 breast cancer cells with low metastasis ability and the treatment with transforming growth factor β1 (TGF-β1) significantly increased the expression of miR-487a in MCF-7 and MDA-MB-231 breast cancer cells. Subsequently, we found that the transfection of miR-487a inhibitor significantly decreased the expression of vimentin, a mesenchymal marker, while increased the expression of E-cadherin, an epithelial marker, in both MCF-7 cells and MDA-MB-231 cells. Also, the inactivation of miR-487a inhibited the migration and invasion of breast cancer cells. Furthermore, our findings demonstrated that miR-487a directly targeted the MAGI2 involved in the stability of PTEN. The down-regulation of miR-487a increased the expression of p-PTEN and PTEN, and reduced the expression of p-AKT in both cell lines. In addition, the results showed that NF-kappaB (p65) significantly increased the miR-487a promoter activity and expression, and TGF-β1 induced the increased miR-487a promoter activity via p65 in MCF-7 cells and MDA-MB-231 cells. Moreover, we further confirmed the expression of miR-487a was positively correlated with the lymph nodes metastasis and negatively correlated with the expression of MAGI2 in human breast cancer tissues. Overall, our results suggested that miR-487a could promote the TGF-β1-induced EMT, the migration and invasion of breast cancer cells by directly targeting MAGI2.

Thursday, September 15, 2016 11:42 PM|Guan Yang, Xiao Yang|International Journal of Biological Sciences|Labels: TGF

Transforming growth factor-β (TGF-β) family members exert their function via specific type I and type II serine/threonine kinase receptors and intracellular Smad transcription factors, including the common mediator Smad4. The dual effects of TGF-β signaling on tumor initiation and progression are cell-specific and yet to be determined under distinct contexts. A number of genetically manipulated mouse models with alterations in the TGF-β pathway genes, particularly the pivotal Smad4, revealed that these genes play crucial functions in maintaining tissue homeostasis and suppressing tumorigenesis. Loss of Smad4 plays a causal role in initiating squamous cell carcinomas of skin and upper digestive tract as well as adenocarcinomas of gastrointestinal tract. However, for some cancers like pancreatic and cholangiocellular carcinomas, Smad4 deficiency does not initiate the tumorigenesis but acts as a promoter to accelerate or synergize the development and progression of cancers that are started by other oncogenic pathways. Intriguingly, emerging evidences from mouse models have highlighted the important roles of non-cell autonomous effects of Smad4-mediated TGF-β signaling in the inhibition of oncogenesis. All these data have greatly deepened our understanding of molecular mechanisms of cell-autonomous and non-cell autonomous effect of Smad4-mediated TGF-β signaling in suppressing carcinogenesis, which may facilitate the development of successful therapies targeting TGF-β signaling for the treatment of human cancers.

Wednesday, September 14, 2016 5:53 PM|Zhi-Yuan Xu, Song-Ming Ding, Lin Zhou, Hai-Yang Xie, Kang-Jie Chen, Wu Zhang, Chun-Yan Xing, Hai-Jun Guo, Shu-Sen Zheng|International Journal of Biological Sciences|Labels: TGF, liver cancer

The existence of microvascular invasion (MVI) formation is one of the most important risk factors predicting poor outcome in hepatocellular carcinoma (HCC) and its mechanism remains largely unknown. Epithelial-Mesenchymal Transition (EMT) has been suggested to be involved in many steps of the invasion-metastasis cascade. To elucidate the possible contribution of EMT to MVI, we initially evaluated the expression of 8 EMT-related transcription factors (TFs) in HCC patients with or without MVI and found that FOXC1 expression was significantly higher in patients with MVI than those without MVI (P < 0.05). Knockdown of FOXC1 expression in HCC cells resulted in a partial conversion of their EMT progresses, mainly regulating the mesenchymal component. Ectopic expression of snail, twist or TGF-β1 could induce expression of FOXC1, but none of the expression of snail, twist, slug or TGF-β was consistently down-regulated in response to FOXC1 silencing, suggesting FOXC1 might operate the downstream of other EMT regulators. In addition, knockdown of FOXC1 expression led to cytoskeleton modification accompanied by decreased ability of cell proliferation, migration, and invasion. Meanwhile, some matrix metalloproteinases (MMPs) and VEGF-A were also simultaneously down-regulated. Together, our findings demonstrate that FOXC1 is one of candidate predictive markers of MVI, and that inhibition of FOXC1 expression can partially reverse EMT program, offering a potential molecular therapeutic target for reducing tumor metastasis in HCC patients.

Wednesday, September 14, 2016 5:53 PM|Erin C. Connolly, Julia Freimuth, Rosemary J. Akhurst|International Journal of Biological Sciences|Labels: TGF

Many advanced tumors produce excessive amounts of Transforming Growth Factor-β (TGF-β) which, in normal epithelial cells, is a potent growth inhibitor. However, in oncogenically activated cells, the homeostatic action of TGF-β is often diverted along alternative pathways. Hence, TGF-β signaling elicits protective or tumor suppressive effects during the early growth-sensitive stages of tumorigenesis. However, later in tumor development when carcinoma cells become refractory to TGF-β-mediated growth inhibition, the tumor cell responds by stimulating pathways with tumor progressing effects. At late stages of malignancy, tumor progression is driven by TGF-β overload. The tumor microenvironment is a target of TGF-β action that stimulates tumor progression via pro-tumorigenic effects on vascular, immune, and fibroblastic cells. Bone is one of the richest sources of TGF-β in the body and a common site for dissemination of breast cancer metastases. Osteoclastic degradation of bone matrix, which accompanies establishment and growth of metastases, triggers further release of bone-derived TGF-β. This leads to a vicious positive feedback of tumor progression, driven by ever increasing levels of TGF-β released from both the tumor and bone matrix. It is for this reason, that pharmaceutical companies have developed therapeutic agents that block TGF-β signaling. Nonetheless, the choice of drug design and dosing strategy can affect the efficacy of TGF-β therapeutics. This review will describe pre-clinical and clinical data of four major classes of TGF-β inhibitor, namely i) ligand traps, ii) antisense oligonucleotides, iii) receptor kinase inhibitors and iv) peptide aptamers. Long term dosing strategies with TGF-β inhibitors may be ill-advised, since this class of drug has potentially highly pleiotropic activity, and development of drug resistance might potentiate tumor progression. Current paradigms for the use of TGF-β inhibitors in oncology have therefore moved towards the use of combinatorial therapies and short term dosing, with considerable promise for the clinic.

Wednesday, September 14, 2016 4:23 PM|K. Chung|JournalTOCs API - Journal of Investigative Dermatology (875 articles)|Labels: TGF, melanoma

487 Expression of metastasis and invasion related molecules in malignant melanoma
J. Kim C. Gilbert, D. Javelaud, A. Mauviel, K. Chung
Journal of Investigative Dermatology, Vol. 136, No. 9 (2016) pp. S243 -
Multiple genetic targets and signaling pathways have been defined in melanoma oncogenesis. Clinically, identifying key pathway molecules related in metastasis and invasion is crucial for planning treatment options. As in other tumor, epithelial to mesenchymal transition like changes has been reported in melanoma tissue and cell line. In our collaborative study, we have investigated the relationship between molecules associated in TGF-beta signaling pathway in different clinical types of melanoma tissue to find association.

Wednesday, September 14, 2016 3:00 PM|Huang-Chun Lien|PLOS ONE Alerts: New Articles|Labels: TGF, breast cancer

by Li-Ching Fan, Yung-Ming Jeng, Yueh-Tong Lu, Huang-Chun Lien

In addition to contraction, myoepithelia have diverse paracrine effects, including a tumor suppression effect. However, certain myoepithelial markers have been shown to contribute to tumor progression. Transforming growth factor-β (TGF-β) is involved in the transdifferentiation of fibroblasts to contractile myofibroblasts. We investigated whether TGF-β can upregulate potential myoepithelial markers, which may have functional and clinicopathological significance in breast cancer. We found that TGF-β induced SPOCK1 expression in MCF10A, MCF12A, and M10 breast cells and demonstrated SPOCK1 as a novel myoepithelial marker that was immunolocalized within or beneath myoepithelia lining ductolobular units. A functional study showed that overexpression of SPOCK1 enhanced invasiveness in mammary immortalized and cancer cells. To further determine the biological significance of SPOCK1 in breast cancer, we investigated the expression of SPOCK1 in 478 invasive ductal carcinoma (IDC) cases through immunohistochemistry and correlated the expression with clinicopathological characteristics. SPOCK1 expression was significantly correlated with high pathological tumor size (P = 0.012), high histological grade (P = 0.013), the triple-negative phenotype (P = 0.022), and the basal-like phenotype (P = 0.026) and was correlated with a significantly poorer overall survival on univariate analysis (P = 0.001, log-rank test). Multivariate Cox regression analysis demonstrated that SPOCK1 expression maintained an independent poor prognostic factor of overall survival. Analysis of SPOCK1 expression on various non-IDC carcinoma subtypes showed an enrichment of SPOCK1 expression in metaplastic carcinoma, which is pathogenetically closely related to epithelial-mesenchymal transition (EMT). In conclusion, we identified SPOCK1 as a novel TGF-β–induced myoepithelial marker and further demonstrated that SPOCK1 enhanced invasion in breast cancer cells and correlated with poor prognosis in breast cancer clinical samples. The enrichment of SPOCK1 expression in metaplastic carcinoma and the correlation between SPOCK1 expression and high histological grading and basal-like phenotypes in IDC evidence an association between SPOCK1 and EMT.
Tuesday, September 13, 2016 8:19 PM|Hao Li, Guangchun He, Hui Yao, Liujiang Song, Liang Zeng, Xiaoning Peng, Thomas J. Rosol, Xiyun Deng|Journal of Cancer (RSS 2.0)|Labels: proteasome, TGF, liver cancer

Both transforming growth factor-β (TGF-β) and parathyroid hormone-related protein (PTHrP) regulate important cellular processes, such as apoptosis in the development of hepatocellular carcinoma. However, the mechanisms of regulation of PTHrP by TGF-β are largely unknown. We hypothesized that TGF-β regulates the expression of PTHrP protein through a post-translational mechanism. Using hepatocellular carcinoma cell lines as the in vitro model, we investigated the effects of TGF-β on protein expression and post-translational processing of PTHrP. We found that TGF-β treatment led to protein degradation of PTHrP through the ubiquitin-proteasome-dependent pathway. We also provided evidence to show that Smurf2 was the E3 ligase responsible for the ubiquitination of PTHrP. Furthermore, using immunohistochemistry on human hepatocellular carcinoma specimens and a tissue array, we found that the expression of PTHrP was predominantly in the cancer cells, whereas the expression of TGF-β was present in non-neoplastic liver tissue adjacent to hepatocellular carcinoma. Our findings reveal a novel mechanism whereby TGF-β may regulate PTHrP in hepatocellular carcinogenesis and lack of TGF-β in hepatocellular carcinoma may promote cancer progression. Promotion of PTHrP degradation provides a novel target of therapeutic intervention to sensitize hepatocellular carcinoma cells to cytostatic and/or pro-apoptotic signals.

Tuesday, September 13, 2016 8:19 PM|Allal Ouhtit, Samineh Madani, Ishita Gupta, Somya Shanmuganathan, Mohamed E. Abdraboh, Hamad Al-Riyami, Yahya M Al-Farsi, Madhwa HG Raj|Journal of Cancer|Labels: TGF, breast cancer

We have developed a tetracycline (tet)-off regulated expression of CD44s gene in the breast cancer (BC) cell line MCF-7 (B5 clone) and identified TGF-β2 (Transforming Growth Factor beta-2; 3 fold induction) as a potential CD44-downstream transcriptional target by microarray analysis. To further validate this finding, the same RNA samples, used for microarray analysis and their corresponding protein lysates, collected from the BC cell line MCF-7-B5, were examined for CD44 expression in the presence of HA. Our results showed that TGF-β2 mRNA levels were significantly elevated following the removal of tetracycline at 18, 24, and 48 h post-HA stimulation compared to the parental cells. Furthermore, the TGF-β2 precursor protein increased in a time-dependent pattern upon HA-stimulation and in the absence of tetracycline. More interestingly, inhibition of CD44 gene by RNAi method decreased TGF-β2 expression upon HA-stimulation, and subsequently inhibited BC cell invasion in vitro. In addition to identifying TGF-β2 as a target for HA/CD44 signaling, this data suggests that ATF/CREB might be a potential transcription factor linking HA/CD44 activation to TGF-β2 transcription and additional experiments are required for a better understanding of the molecular mechanisms underpinning the novel function of the CD44/ TGF-β2 signaling pathway in breast cancer metastasis.

Tuesday, September 13, 2016 2:05 PM|Artur Jurczyszyn, Jacek Czepiel, Grażyna Biesiada, Joanna Gdula-Argasińska, Dorota Cibor, Danuta Owczarek, William Perucki, Aleksander B. Skotnicki|Journal of Cancer|Labels: TGF, VEGF, MM

Background. In the last few years, it has been widely reported that proinflammatory and angiogenic cytokines are important for the development and progression of multiple myeloma (MM).

Objectives. To further validate and acquire more insight into this view we decided to check whether plasma levels of certain cytokines and their soluble receptors differ between MM patients and healthy subjects.

Patients and Methods. The study was conducted in 76 MM patients aged 22 to 77 years (60±10 years) and 35 healthy controls aged 20 to 63 years (33±10 years). Plasma levels of interleukin-6 (IL-6), b-fibroblast growth factor (b-FGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1), as well as soluble receptors for IL-6 (sIL-6R) and VEGF (sVEGF-R2) were measured using enzyme-linked immunosorbent assay (ELISA).

Results. Significantly higher plasma levels of IL-6 (13.65±42.61 vs. 1.04±1.12 pg/ml, p=0.006), HGF (2174±2714 vs. 648±130 pg/ml, p<0.001), b-FGF (7.92±10.78 vs. 2.54±5.38 pg/ml, p<0.001) and sIL-6R (37.1±14.2 vs. 25.3±6.4 ng/ml, p=0.003) were observed in MM patients vs. healthy controls, respectively. Plasma sVEGF-R2 was significantly lower in MM patients than in controls (7518±2119 vs. 8725±1281 pg/ml, respectively; p<0.001). We observed an inverse correlation between length of treatment and the level of sIL-6R, and TGF-β1 in plasma.

Conclusions. Plasma levels of HGF, b-FGF, IL-6 and sIL-6R in MM patients were higher ​​when compared to the control group. Antineoplastic therapy leads to a time-dependent decrease in plasma levels of sIL-6R, and TGF-β1 in MM patients. Blood plasma level of HGF is an optimal measure to differentiate patients in whom disease is progressing versus patients who respond to therapy.

Friday, August 26, 2016 1:20 PM|Elsevier|JournalTOCs API - Biochemical and Biophysical Research Communications (50 articles)|Labels: TGF, lung cancer

Exosome cargo reflects TGF-β1-mediated epithelial-to-mesenchymal transition (EMT) status in A549 human lung adenocarcinoma cells

Biochemical and Biophysical Research Communications, Vol. , No. (2016) pp. -
Publication date: 16 September 2016 Source:Biochemical and Biophysical Research Communications, Volume 478, Issue 2 Author(s): Jiyeon Kim, Tae Yeon Kim, Myung Shin Lee, Ji Young Mun, Chunhwa Ihm, Soon Ae Kim It has been suggested that tumor cells secrete exosomes to modify the local microenvironment, which then promotes intercellular communication and metastasis. Although exosomes derived from cancer cells may contribute to the epithelial–mesenchymal transition (EMT) in untransformed cells, few studies have defined exosome cargo upon induction of EMT. In this study, we investigated the changes in exosomal cargo from the epithelial to mesenchymal cell phenotype by inducing EMT with transforming growth factor (TGF)-β1 in A549 human lung adenocarcinoma cells. The protein content of the exosomes reflects the change in the cell phenotype. In addition, miR-23a was significantly enriched in the exosomes after mesenchymal transition. Following treatment of exosomes from mesenchymal cells via EMT induction with TGF-β1 to the epithelial cell type, phenotypic changes in protein expression level and cell morphology were observed. Autologous treatment of exosomes enhanced the transcriptional activity and abundance of β-catenin. Our results suggest that the exosomal protein and miRNA content reflects the physiological condition of its source and that exosomes induce phenotypic changes via autocrine signaling.

Friday, August 12, 2016 12:58 PM|Kang, Y., Roife, D., Lee, Y., Lv, H., Suzuki, R., Ling, J., Rios Perez, M. V., Li, X., Dai, B., Pratt, M., Truty, M. J., Chatterjee, D., Wang, H., Thomas, R. M., Wang, Y., Koay, E. J., Chiao, P. J., Katz, M. H., Fleming, J. B.|Clinical Cancer Research Online First Articles|Labels: TGF, pancreatic cancer

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is lethal cancer whose primary tumor is characterized by dense composition of cancer cells, stromal cells, and extracellular matrix (ECM) composed largely of collagen. Within the PDAC tumor microenvironment, activated pancreatic stellate cells (PSC) are the dominant stromal cell type and responsible for collagen deposition. Lumican is a secreted proteoglycan that regulates collagen fibril assembly. We have previously identified that the presence of lumican in the ECM surrounding PDAC cells is associated with improved patient outcome after multimodal therapy and surgical removal of localized PDAC.

Experimental Design: Lumican expression in PDAC from 27 patients was determined by IHC and quantitatively analyzed for colocalization with PSCs. In vitro studies examined the molecular mechanisms of lumican transcription and secretion from PSCs (HPSCs and HPaSteC), and cell adhesion and migration assays examined the effect of lumican on PSCs in a collagen-rich environment.

Results: Here we identify PSCs as a significant source of extracellular lumican production through quantitative IHC analysis. We demonstrate that the cytokine, TGF-β, negatively regulates lumican gene transcription within HPSCs through its canonical signaling pathway and binding of SMAD4 to novel SBEs identified within the promoter region. In addition, we found that the ability of HPSCs to produce and secrete extracellular lumican significantly enhances HPSCs adhesion and mobility on collagen.

Conclusions: Our results demonstrate that activated pancreatic stellate cells within PDAC secrete lumican under the negative control of TGF-β; once secreted, the extracellular lumican enhances stellate cell adhesion and mobility in a collagen-rich environment. Clin Cancer Res; 1–13. ©2016 AACR.

Thursday, July 28, 2016 7:56 AM|McCann, J. V., Xiao, L., Khan, O., Kowalski, P., Azam, S., Pecot, C. V., Anderson, D. G., Dudley, A. C.|Cancer Research recent issues|Labels: TGF, pancreatic cancer
Tumor-associated endothelial cells (TECs) are dysfunctional and leak fibrin which is resolved (fibrinolysis) and replaced with collagen in a process that closely resembles wound healing. Because degraded perivascular fibrin also promotes angiogenesis and creates scaffolds for invasive cancer cells, vascular-directed fibrinolysis in solid tumors is a fundamental spark during tumor progression. Using a miRNA screen of freshly isolated TECs, we identified a TGF beta-regulated miRNA that controls vascular-mediated fibrinolysis in tumors. miR-30c is increased in TECs relative to normal endothelial cells (NECs) whereas its target PAI-1 (a fibrinolysis inhibitor) is strikingly decreased. TECs secrete less PAI-1 and they rapidly degrade and migrate through fibrin scaffolds resulting in uncoordinated vessel sprouting. However, TGF beta and miR-30c antagomiRs reduce miR-30c expression which re-instates PAI-1 secretion, diminishes vascular-specific fibrinolysis, and “normalizes” TEC sprouting. miR-30c antagomiRs coupled to vascular-tropic nanoparticles reduce TEC migration in fibrin and enforce vascular expression of PAI-1 in vitro and in vivo. Thus, vascular-specific expression of miR-30c in tumors may be manipulated in vivo using this nanoparticle-based strategy. We also show that TGF beta promotes the export of miR-30c in extracellular vesicles (EVs) which are received by recipient stromal cells. TGF beta-mediated extravascular mobilization of miR-30c may down regulate PAI-1 expression in nearby stromal cells or cancer cells thereby programing fibrinolysis in these non-vascular recipients. Taken together, we propose an axis between TGF beta, miR-30c, and PAI-1 in TECs controls the rate of perivascular fibrinolysis and is therefore an important effector of tumor emergence.Citation Format: James V. McCann, Lin Xiao, Omar Khan, Piotr Kowalski, Salma Azam, Chad V. Pecot, Daniel G. Anderson, Andrew C. Dudley. miR-30c: a TGF beta-regulated miRNA that coordinates vascular-directed fibrinolysis and tumor angiogenesis. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A47.
Thursday, July 28, 2016 7:56 AM|Pitarresi, J. R., Ostrowski, M. C.|Cancer Research recent issues|Labels: Hh/SMO, TGF, pancreatic cancer
Purpose of Study: Pancreatic cancer is an overwhelming fatal disease with less than 5% of patients surviving beyond 5 years. The most prominent histopathological hallmark of pancreatic cancer is its uniquely dense stromal reaction as evidenced by recent reports that highlight the significant role of stromal fibroblasts on pancreatic tumor cell biology. We used novel mouse models to show that genetic inactivation of Smoothened (Smo) in stromal fibroblasts accelerated Kras-initiated tumorigenesis.Research Method: We used a genetically engineered mouse model of pancreatic cancer that relies on constitutive activation of the Kras oncogene in the epithelium. We simultaneously employed cre-loxP technology to conditionally delete Smo exclusively in the fibroblast compartment of the pancreas, thus disrupting the crucial hedgehog paracrine signaling loop between pancreatic tumor cells and fibroblasts.Novel Findings: We showed that deletion of Smo in stromal fibroblasts accelerated pancreatic tumorigenesis through a mechanism involving destabilization of fibroblast PTEN protein. Down-regulation of PTEN enhanced TGF-α production in stromal fibroblasts, and increased epithelial cell transformation and proliferation through epithelial growth factor receptor (EGFR). A selective SMO inhibitor also decreased PTEN in a Kras mouse model as well as in human primary pancreatic cancer associated fibroblasts. Importantly, in pancreatic ductal adenocarcinoma (PDAC) patient samples, low PTEN expression correlated with low SMO expression and with reduced overall survival. These results define a pathway that reprograms stromal fibroblasts from a tumor suppressive phenotype to a tumor promoting phenotype, thus highlighting the dual functions of stromal fibroblasts in pancreatic cancer and the molecular consequences of loss of the hedgehog pathway. Thus, a more comprehensive understanding of tumor-stroma interactions is required to assure effective implementation of targeted therapies.Conclusions and Implications: Recent pre-clinical reports suggest the pancreatic tumor microenvironment functions predominantly to inhibit tumor growth, challenging the concept of tumor stroma as a therapeutic target. Our results provide molecular insight into how the balance between the opposing activities of tumor stromal fibroblasts is maintained, and potentially identifies targets for restoring stromal tumor suppressive functions. In summary, we demonstrate that ablation of paracrine hedgehog signaling in SMA-positive fibroblasts leads to proteasome-mediated degradation of the PTEN tumor suppressor protein and subsequent activation of oncogenic pathways.Citation Format: Jason R. Pitarresi, Michael C. Ostrowski. Genetic ablation of Smoothened in tumor-associated fibroblasts promotes pancreatic tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A40.
Tuesday, March 22, 2016 5:00 AM|Dave Levitan|Chronic Myeloid Leukemia on Cancer Network|Labels: TGF, CML, IL
Elevated levels of TGF-α and IL-6 in newly diagnosed chronic-phase chronic myeloid leukemia patients were predictive of failure to achieve molecular response.
Saturday, March 19, 2016 10:53 AM|Oncology Reports|MedWorm: Cancer Therapy|Comments|Labels: Src, TGF, lung cancer
Authors: Da C, Liu Y, Zhan Y, Liu K, Wang R Abstract Epithelial-mesenchymal transition (EMT) is a critical cellular process in cancer metastasis, during which epithelial polarized cells become motile mesenchymal cells. Since transforming growth factor-β (TGF-β) is a potent inducer of EMT, blocking of TGF-β/Smad signaling has become a promising cancer therapy. Nobiletin, a polymethoxy flavonoid from Citrus depressa, has been shown to be valuable for cancer treatment, yet the mechanism remains unclear. In the present study, lung adenocarcinoma A549 and H1299 cells were used to evaluate the effect of nobiletin on EMT induced by TGF-β1. Nobiletin successfully inhibited TGF-β1-induced EMT, migration, invasion and adhesion in vitro, accompanied by attenuation of MMP-2, MMP-9, p-Src...
Authors: Rateitschak K, Kaderali L, Wolkenhauer O, Jaster R Abstract The epithelial-mesenchymal transition (EMT) is the crucial step that cancer cells must pass before they can undergo metastasis. The transition requires the activity of complex functional networks that downregulate properties of the epithelial phenotype and upregulate characteristics of the mesenchymal phenotype. The networks frequently include reciprocal repressions between transcription factors (TFs) driving the EMT and microRNAs (miRs) inducing the reverse process, termed mesenchymal-epithelial transition (MET). In this work we develop four kinetic models that are based on experimental data and hypotheses describing how autocrine transforming growth factor-β (TGF-β) signal transduction induces and maintains an...
Friday, February 26, 2016 4:00 PM|Lung Cancer|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, TGF, lung cancer
The epidermal growth factor receptor (EGFR) is a member of the HER family of receptor tyrosine kinases, and EGF and transforming growth factor-alpha (TGF-α) are ligands that bind to the extracellular domain of the EGFR. The binding of ligands induces a conformational change and dimerization of the receptor and subsequently, leads to the activation of its intracellular tyrosine kinase domain [1]. The following cascade of intracellular events results in cell proliferation, invasion, metastasis, and angiogenesis [1]. (Source: Lung Cancer)
Thursday, February 25, 2016 10:21 AM|Shapira, I., Bhuiya, T., Arora, S., Mukhi, N., Datla, S., Neculiseanu, E., Mason, C., Shih, A., Lee, A.|Journal of Investigative Medicine recent issues|Labels: BRCA, TGF, breast cancer
Purpose of Study

Over 240,000 individuals are diagnosed with breast cancer (BrCa) of which 12,000 individuals carry BRCA germline mutations. MicroRNA dysregulation is common in malignancy and may correlate with germline mutations.

Aims:

1. Analyze microRNAs in patients with breast cancer with or without BRCA germ line mutations, with and without cancer.

2. Identify molecular BRCA mutant patients to deduct reasons for accelerated malignancy.

Methods Used

We analyzed plasma miR expression from 94 br cancer patients (41 BRCA positive) relative to 24 normal controls. All samples were collected between 2010 and 2014 and survival data was known for all cancer patients. TaqMan Open Array panel was used to simultaneously run hundreds of microRNA assays in the Applied Biosystem Open array real time PCR. Using AB open array real time PCR, 756 miRNA species were detected. Two-sample t-test was used for all 2-sample comparison and ANOVA followed by Tukey HSD post-hoc test to compare the miRs mean differences. All tests were 2-tailed and results with a p<0.05 were considered statistically significant.

Summary of Results

BRCA+underexpressed hsa-mir-10a and hsa-mir-376c and over-expressed Hsa- mir- 326 and Hsa-mir-143 relative to BRCA-; p<0.05.

Using Coremine data mining linking genes and diseases differentially expressed circulating miRs are linked to tumor suppressor TGFbeta/SMAD3.

Conclusions

The early onset of breast cancer in BRCA mutant patients may recapitulate the pro-oncogenic effects of TGF-β. The context dependent SMAD3 binding & tumor suppression TGF-β effects are abrogated in BRCA mutant patients. TGF-β/Smad3 tumor-suppressor signature suppresses local inflammation in the tumor microenvironment.

Tuesday, February 23, 2016 4:00 PM|Carcinogenesis|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: TGF, lung cancer
Increasing evidence shows that micro RNAs (miRNAs) play a critical role in tumor development. However, the role of miRNAs in non-small cell lung cancer (NSCLC) metastasis remains largely unknown. Here, we found that miR-124 expression was significantly impaired in NSCLC tissues and associated with its metastasis. In vitro and in vivo experiments indicate that restoring miR-124 expression in NSCLC cells had a marked effect on reducing cell migration, invasion and metastasis. Mechanistic analyses show that Smad4, a cobinding protein in transforming growth factor-β (TGF-β) pathway, was identified as a new target gene of miR-124. Restoring Smad4 expression in miR-124-infected cells could partially rescue miR-124-induced abolition of cell migration and invasion. Notably, upon TGF-&bet...
Tuesday, January 19, 2016 4:00 PM|PLoS One|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, TGF, lung cancer
by Takeshi Yoshida, Lanxi Song, Yun Bai, Fumi Kinose, Jiannong Li, Kim C. Ohaegbulam, Teresita Muñoz-Antonia, Xiaotao Qu, Steven Eschrich, Hidetaka Uramoto, Fumihiro Tanaka, Patrick Nasarre, Robert M. Gemmill, Joëlle Roche, Harry A. Drabkin, Eric B. Haura Epithelial-mesenchymal transition (EMT) is one mechanism of acquired resistance to inhibitors of the epidermal growth factor receptor-tyrosine kinases (EGFR-TKIs) in non-small cell lung cancer (NSCLC). The precise mechanisms of EMT-related acquired resistance to EGFR-TKIs in NSCLC remain unclear. We generated erlotinib-resistant HCC4006 cells (HCC4006ER) by chronic exposure of EGFR-mutant HCC4006 cells to increasing concentrations of erlotinib. HCC4006ER cells acquired an EMT phenotype and activation of the TGF-β/SMAD pathway, while l...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, EGFR, TGF, lung cancer
Alectinib is a highly selective ALK inhibitor and shows promising efficacy in non–small cell lung cancers (NSCLC) harboring the EML4-ALK gene rearrangement. The precise mechanism of acquired resistance to alectinib is not well defined. The purpose of this study was to clarify the mechanism of acquired resistance to alectinib in ALK-translocated lung cancer cells. We established alectinib-resistant cells (H3122-AR) from the H3122 NSCLC cell line, harboring the EML4-ALK gene rearrangement, by long-term exposure to alectinib. The mechanism of acquired resistance to alectinib in H3122-AR cells was evaluated by phospho-receptor tyrosine kinase (phospho-RTK) array screening and Western blotting. No mutation of the ALK-TK domain was found. Phospho-RTK array analysis revealed that the phosph...

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