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Stroma cancer colon

Chunmei Piao, Wen-Mei Zhang, Tao-Tao Li, Cong-Cong Zhang, Shulan Qiu, Yan Liu, Sa Liu, Ming Jin, Li-Xin Jia, Wen-Chao Song, Jie Du
Inflammatory cells such as macrophages can play a pro-tumorigenic role in the tumor stroma. Tumor-associated macrophages (TAMs) generally display an M2 phenotype with tumor-promoting activity; however, the mechanisms regulating the TAM phenotype remain unclear. Complement 5a (C5a) is a cytokine-like polypeptide that is generated during complement system activation and is known to promote tumor growth. Herein, we investigated the role of C5a on macrophage polarization in colon cancer metastasis in mice. We found that deficiency of the C5a receptor (C5aR) severely impairs the metastatic ability of implanted colon cancer cells...
March 15, 2018: Experimental Cell Research
Michael K Dame, Durga Attili, Shannon D McClintock, Priya H Dedhia, Peter Ouillette, Olaf Hardt, Alana M Chin, Xiang Xue, Julie Laliberte, Erica L Katz, Gina M Newsome, David R Hill, Alyssa J Miller, Yu-Hwai Tsai, David Agorku, Christopher H Altheim, Andreas Bosio, Becky Simon, Linda C Samuelson, Jay A Stoerker, Henry D Appelman, James Varani, Max S Wicha, Dean E Brenner, Yatrik M Shah, Jason R Spence, Justin A Colacino
The intestine is maintained by stem cells located at the base of crypts and distinguished by the expression of LGR5. Genetically engineered mouse models have provided a wealth of information about intestinal stem cells, while less is known about human intestinal stem cells due to difficulty detecting and isolating these cells. We established an organoid repository from patient-derived adenomas, adenocarcinomas, and normal colon, which we analyzed for variants in 71 colorectal cancer (CRC) associated genes. Normal and neoplastic colon tissue organoids were analyzed by immunohistochemistry and fluorescent-activated cell sorting for LGR5...
February 21, 2018: Development
Moritz F Eissmann, Christine Dijkstra, Merridee A Wouters, David Baloyan, Dmitri Mouradov, Paul M Nguyen, Mercedes Davalos-Salas, Tracy L Putoczki, Oliver M Sieber, John M Mariadason, Matthias Ernst, Frederick Masson
Interleukin 33 (IL33) is an inflammatory cytokine released during necrotic cell death. The epithelium and stroma of the intestine express large amounts of IL33 and its receptor St2. IL33 is therefore continuously released during homeostatic turnover of the intestinal mucosa. Although IL33 can prevent colon cancer associated with inflammatory colitis, the contribution of IL33 signaling to sporadic colon cancer remains unknown. Here, we utilized a mouse model of sporadic colon cancer to investigate the contribution of IL33 signaling to tumorigenesis in the absence of pre-existing inflammation...
February 20, 2018: Cancer Immunology Research
Gabi W van Pelt, Tessa P Sandberg, Hans Morreau, Hans Gelderblom, J Han J M van Krieken, Rob A E M Tollenaar, Wilma E Mesker
The tumour microenvironment consists of a complex mixture of non-neoplastic cells including fibroblasts, immune cells and endothelial cells embedded in the proteins of the extracellular matrix. The tumour microenvironment plays an active role in tumour behaviour. By interacting with cancer cells, it influences disease progression and the metastatic capacity of the tumour. Tumours with a high amount of stroma correspond to poor patient prognosis. The tumour-stroma ratio (TSR) is a strong independent prognostic tool in colon cancer and provides additional value to the current clinically used TNM classification...
February 19, 2018: Histopathology
Anouck Huijbers, Gabi W van Pelt, Rachel S Kerr, Elaine C Johnstone, Rob A E M Tollenaar, David J Kerr, Wilma E Mesker
INTRODUCTION: Patients with a high stroma percentage within the primary tumor have a poor prognosis. In this study, we investigate whether anti-angiogenic therapy might improve survival of patients with a stroma-high profile with potentially increased angiogenesis. MATERIALS AND METHODS: Tissue samples of the primary tumor of 965 colon cancer patients participating in the QUASAR2 trial were analyzed for tumor-stroma ratio (TSR). Stroma-high (>50%) and stroma-low (≤50%) groups were evaluated with respect to survival...
February 15, 2018: Journal of Surgical Oncology
Mariano Colón-Caraballo, Annelyn Torres-Reverón, John Lee Soto-Vargas, Steven Young, Bruce Lessey, Adalberto Mendoza, Raúl Urrutia, Idhaliz Flores
Although the histone methyltransferase EZH2 and its product H3K27me3 are well studied in cancer, little is known about their role and potential as therapeutic targets in endometriosis. We have previously reported that endometriotic lesions are characterized by global enrichment of H3K27me3. Therefore, we aimed to 1) characterize the expression levels of EZH2 in endometriotic tissues, 2) assess H3K27me3 enrichment in candidate genes promoter regions, and 3) determine if pharmacological inhibition of EZH2 impacts migration, proliferation, and invasion of endometriotic cells...
February 2, 2018: Biology of Reproduction
Eddie Han Pin Tan, Ming Keat Sng, Ivan Shun Bo How, Jeremy Soon Kiat Chan, Jiapeng Chen, Chek Kun Tan, Walter Wahli, Nguan Soon Tan
Tumor stroma has an active role in the initiation, growth, and propagation of many tumor types by secreting growth factors and modulating redox status of the microenvironment. Although PPARβ/δ in fibroblasts was shown to modulate oxidative stress in the wound microenvironment, there has been no evidence of a similar effect in the tumor stroma. Here, we present evidence of oxidative stress modulation by intestinal stromal PPARβ/δ, using a FSPCre-Pparb/d-/- mouse model and validated it with immortalized cell lines...
January 25, 2018: Oncogene
Arseniy E Yuzhalin, Tomas Urbonas, Michael A Silva, Ruth J Muschel, Alex N Gordon-Weeks
BACKGROUND: Accumulating evidence implicates the tumour stroma as an important determinant of cancer progression but the protein constituents relevant for this effect are unknown. Here we utilised a bioinformatics approach to identify an extracellular matrix (ECM) gene signature overexpressed in multiple cancer types and strongly predictive of adverse outcome. METHODS: Gene expression levels in cancers were determined using Oncomine. Geneset enrichment analysis was performed using the Broad Institute desktop application...
January 23, 2018: British Journal of Cancer
Folashade Otegbeye, Evelyn Ojo, Stephen Moreton, Nathan Mackowski, Dean A Lee, Marcos de Lima, David N Wald
Natural killer cells harnessed from healthy individuals can be expanded ex vivo using various platforms to produce large doses for adoptive transfer into cancer patients. During such expansion, NK cells are increasingly activated and more efficient at killing cancer cells. Adoptive transfer however introduces these activated cells into a highly immunosuppressive tumor microenvironment mediated in part by excessive transforming growth factor beta (TGF-beta) from both cancer cells and their surrounding stroma...
2018: PloS One
Guanghua Liu, Shi Feng, Lin Jia, Chunying Wang, Yan Fu, Yongzhang Luo
As a rate-limiting step in metastasis, metastatic colonization requires survival signals from supportive stroma. However, the mechanisms driving this process are incompletely understood. Here, we showed that the proliferation of B16F10 cells was promoted when cocultured with lung fibroblasts. Meanwhile, co-injection of B16F10 tumor cells with mouse lung fibroblasts significantly increased lung metastasis. Based on GEO database, we identified stearoyl-CoA desaturase 1 (SCD1) as a novel factor promoting metastatic colonization...
January 12, 2018: Oncogene
James Ziai, Houston N Gilbert, Oded Foreman, Jeffrey Eastham-Anderson, Felix Chu, Mahrukh Huseni, Jeong M Kim
The prevalence of cytotoxic tumor infiltrating lymphocytes (TILs) has demonstrated prognostic value in multiple tumor types. In particular, CD8 counts (in combination with CD3 and CD45RO) have been shown to be superior to traditional UICC staging in colon cancer patients and higher total CD8 counts have been associated with better survival in breast cancer patients. However, immune infiltrate heterogeneity can lead to potentially significant misrepresentations of marker prevalence in routine histologic sections...
2018: PloS One
Sergio Alonso, Beatriz González, Andreu Alibés, Manuel Perucho
The genome of cancer cells accumulates numerous genetic and epigenetic somatic alterations ultimately conferring capabilities for unrestrained growth, invasion of local tissues, migration, and colonization of distant organs. Many of these new capabilities require the disruption of the cell-to-cell interactions between the cancer cell and its microenvironment. These interactions are mediated, among other factors, by the activity of extracellular enzymes that reshape not only the extracellular compartment of the cancer cells but also that of the neighboring non-cancerous stroma cells...
2018: Methods in Molecular Biology
Jatin Roper, Tuomas Tammela, Adam Akkad, Mohammad Almeqdadi, Sebastian B Santos, Tyler Jacks, Ömer H Yilmaz
Most genetically engineered mouse models (GEMMs) of colorectal cancer are limited by tumor formation in the small intestine, a high tumor burden that limits metastasis, and the need to generate and cross mutant mice. Cell line or organoid transplantation models generally produce tumors in ectopic locations-such as the subcutaneous space, kidney capsule, or cecal wall-that do not reflect the native stromal environment of the colon mucosa. Here, we describe detailed protocols to rapidly and efficiently induce site-directed tumors in the distal colon of mice that are based on colonoscopy-guided mucosal injection...
February 2018: Nature Protocols
Adrian G Murphy, Kelly Foley, Agnieszka A Rucki, Tao Xia, Elizabeth M Jaffee, Chiung-Yu Huang, Lei Zheng
Pancreatic ductal adenocarcinoma (PDA) is renowned for high rates of metastasis and poor survival. Its notoriously dense fibrotic stroma contributes to chemoresistance. Stromal signaling in PDA is recognized for its multiple roles in regulating tumor invasion and metastasis. However, no stromal biomarker which can predict survival in PDA exists. Annexin A2 (AnxA2) was formerly identified as a metastasis-associated protein in PDA and tumoral overexpression is associated with poor survival. In this study, we examined AnxA2 expression in the tumor microenvironment in a preclinical model of PDA which suggests its role in tumor colonization...
December 5, 2017: Oncotarget
Jérôme Raffenne, Jérôme Cros
Multi-omics high throughput analyses lead to the description of multiple molecular subtypes of pancreatic adenocarcinoma with major prognostic impact for most of them. There is no consensual multilevel integrative classification yet like in colon or breast cancers. Genomic classifications have identified a tumor subtype (15% of the patients) with deficient homologous DNA repair-system leading to increase sensitivity to platinum-based therapies and possibly to PARP inhibitors and immunotherapies. Transcriptomic classifications are still debated but all have identified an aggressive subtype with a very poor prognosis, presumably unfit for a surgical approach...
December 19, 2017: Bulletin du Cancer
Tomohiro Aoki, Shuh Narumiya
Background: Colorectal cancer is the third most common cancer. Involvement of prostaglandin (PG) system in the pathogenesis of colorectal cancer has been suggested from clinical studies demonstrating therapeutic effect of NSAIDs including aspirin or selective COX-2 inhibitors. However, mechanisms on how PG regulates inflammatory responses leading to colorectal cancer development remain obscure. Further, careful attention is needed to use these drugs for a long time because of adverse effects due to non-specific inhibition of physiological PG production in addition to pathological one, making the development of alternatives to aspirin important...
2017: Inflammation and Regeneration
Shane R Horman, Jeremy To, John Lamb, Jocelyn H Zoll, Nicole Leonetti, Buu Tu, Rita Moran, Robbin Newlin, John R Walker, Anthony P Orth
Recent advances in chemotherapeutics highlight the importance of molecularly-targeted perturbagens. Although these therapies typically address dysregulated cancer cell proteins, there are increasing therapeutic modalities that take into consideration cancer cell-extrinsic factors. Targeting components of tumor stroma such as vascular or immune cells has been shown to represent an efficacious approach in cancer treatment. Cancer-associated fibroblasts (CAFs) exemplify an important stromal component that can be exploited in targeted therapeutics, though their employment in drug discovery campaigns has been relatively minimal due to technical logistics in assaying for CAF-tumor interactions...
November 21, 2017: Oncotarget
Tomokatsu Omoto, Joo-Ri Kim-Kaneyama, Xiao-Feng Lei, Akira Orimo, Koji Ohnishi, Kosuke Yoshihara, Aya Miyauchi, Shuo Li, Lin Gao, Takahiro Umemoto, Junichi Tanaka, Kenta Nakahara, Motohiro Takeya, Fumio Ishida, Shin-Ei Kudo, Shogo Haraguchi, Takuro Miyazaki, Akira Miyazaki
Carcinoma-associated fibroblasts (CAFs) influence tumor initiation, progression, and metastasis within the tumor-associated stroma. This suggests that CAFs would be a potential target for tumor therapy. Here we found that Hydrogen peroxide-inducible clone-5 (Hic-5), also named transforming growth factor beta-1-induced transcript 1 protein (Tgfb1i1), was strongly induced in CAFs found in human colorectal cancer. To investigate the role of Hic-5 in CAFs, we isolated CAFs and the control counterpart normal fibroblasts (NFs) from human colorectal cancer and non-cancerous regions, respectively...
December 15, 2017: Oncogene
Larissa Kistner, Dietrich Doll, Anne Holtorf, Ulrich Nitsche, Klaus-Peter Janssen
Tumor-infiltrating T-cells are strongly associated with prognosis in colorectal cancer, but the mechanisms governing intratumoral lymphocyte recruitment are unclear. We investigated the clinical relevance and functional contribution of interferon-regulated CXC-chemokines CXCL9, CXCL10, and CXCL11, described as T-cells attractants. Their expression was significantly elevated in tumors as compared to normal colon in 163 patients with colon cancer, represented an independent positive predictor of post-operative survival, and was highly significantly correlated with the presence of tumor-infiltrating cytotoxic CD8+ T-cells and CD4+ TH1 -effector cells...
October 27, 2017: Oncotarget
Núria Niell, María Jesús Larriba, Gemma Ferrer-Mayorga, Isabel Sánchez-Pérez, Ramón Cantero, Francisco X Real, Luis Del Peso, Alberto Muñoz, José Manuel González-Sancho
Colorectal cancer results from the malignant transformation of colonic epithelial cells. Stromal fibroblasts are the main component of the tumour microenvironment, and play an important role in the progression of this and other neoplasias. Wnt/β-catenin signalling is essential for colon homeostasis, but aberrant, constitutive activation of this pathway is a hallmark of colorectal cancer. Here we present the first transcriptomic study on the effect of a Wnt factor on human colonic myofibroblasts. Wnt3A regulates the expression of 1,136 genes, of which 662 are upregulated and 474 are downregulated in CCD-18Co cells...
October 16, 2017: International Journal of Cancer. Journal International du Cancer
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