Genome wide analysis of skin cancer cell gene expresison exposed to stromal cancer associated fibroblasts in 3D gel matrix
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Hemant Kocher
PROVIDER: E-GEOD-36776 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:SCC12 cells were seeded ontop of organotypic gels with HN-CAF (head and neck carcinoma associated fibroblasts). Differential gene expression was analysed between cancer cells not exposed to CAFs or non-invading cancer cells exposed to CAFs.
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Project description:The first step in metastasis is dissemination of tumor cells into the surrounding tissue, or stroma. In carcinomas, cancers of epithelial origin, tumor cells must first breach the basement membrane (BM), a network that encapsulates the tumor. As tumor progresses, other cell types that reside in the stroma, such as carcinoma-associated fibroblasts (CAFs) accumulate around the tumor. Whether CAFs can help cancer cells to breach the BM remains an open question. Here we show that CAFs promote cancer cell invasion by physically remodeling the BM. Using a novel 3D in vitro model we observed that primary CAFs isolated from colon cancer patients stimulate cancer cell invasion through a native mesenteric BM. This stimulated invasion is the result of the physical presence of CAFs rather than an increased invasive potential of cancer cells. In the presence of CAFs, cancer cells can invade the BM in a matrix metalloproteinase-independent manner. Using live imaging, we found that CAFs actively pull and stretch the BM, leading to the formation of gaps through which cancer cells can migrate. Notably, CAF-mediated gap-widening is independent of proteolysis but relies on actomyosin contractility. We propose that CAFs exert mechanical forces that alter the organization and the physical properties of the BM, making it permissive for cancer cell invasion.
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Project description:Cancer-associated fibroblasts (CAFs) are an important component of the desmoplastic stroma in rectal cancer. Preoperative chemoradiotherapy plays a pivotal role in the management of locally advanced rectal cancer. Patient-derived CAFs were used to evaluate the response to radiotherapy and its consequent impact on colorectal cancer cells (COLO320DM). COLO320DM cells were seeded and 24 hours later 1.8Gy irradiated. Subsequently, 24h later COLO320DM cells were treated with the secretome of 10x 1.8Gy irradiated CAFs or sham treated CAFs in 0.5% of serum. RNA was isolated 6 hours or 48 hours later.
2017-11-01 | E-MTAB-5364 | biostudies-arrayexpress
Project description:Cancer-associated fibroblasts (CAFs) have been reported to support tumor progression by a variety of mechanisms. However, their role in the progression of non-small cell lung cancer (NSCLC) remains poorly defined. In addition, the extent to which specific proteins secreted by CAFs contribute directly to tumor growth is unclear. To study the role of CAFs in NSCLC, a cross-species functional characterization of mouse and human lung CAFs was performed, including gene expression analysis comparing normal mouse lung fibroblasts (NFs) and mouse lung CAFs to seek for differentially-expressed secreted proteins. Gene expression microarrays were used to identify transcriptomic changes between NFs and CAFs that may contribute to their different tumor-enhancing capacity. NFs and CAFs were grown in vitro for RNA extraction and hybridization on mouse 430_2 Affymetrix microarrays
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Project description:Cancer Associated Fibroblasts (CAFs) are crucial in the genesis and progression of tumors. Cervical CAFs (C-CAFs) are less well characterized. Estrogen (E2) is considered a cofactor in cervical carcinogenesis. We studied the molecular signature of exvivo cultured C-CAFs from 4 early International Federation of Gynaecology and Obstetrics (FIGO, IB2) and 2 late (IIIA) stage disease using gene expression microarray. We found C-CAFs to be both pro-tumorigenic and moderately inflammatory; late stage C-CAFs were more actively metabolizing, and cycling, but expressed fewer genes related to immune function. We investigated the expression of ERα in exvivo cultured C-CAFs and studied the role of E2 in their biology by gene expression microarray in the presence of two ERα antagonists: ICI 182,780 and Methyl Piperidino Pyrazole (MPP). Both modulated C-CAF function by down regulating genes associated with cell cycle and metabolism, affecting angiogenesis and cancer progression, though their transcriptomes differed. MPP also down regulated genes involved in Epithelial to Mesenchymal Transition. Thus, canonical ERα signaling is vital for C-CAF functioning. Interfering with paracrine signaling through fibroblast ERα may be worth exploiting as a targeted therapy in cervical cancer. Gene expression microarray profiling of 4 early-stage E2 (estrogen) treated, 2 late-stage E2 treated, 2 early-stage ICI (ER-alpha antagonist) treated, 2 late-stage ICI treated and 2 early-stage MPP (ER-alpha antagonist) treated cervical cancer CAFs. E2 treated C-CAFs served as control.
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2016-03-09 | E-GEOD-78982 | biostudies-arrayexpress
Project description:Carcinoma-associated fibroblasts (CAFs) that express ?-smooth-muscle-actin (?SMA+) contribute to cancer progression, but their precise origin and role in tumorigenesis is not established. Using mouse models of inflammation-induced gastric cancer, we show that at least 20% of CAFs originate from bone marrow and derive from mesenchymal stem cells (MSCs). Surprisingly, we find that ?SMA+ myofibroblasts (MF) are niche cells normally present in bone marrow and increase markedly in the bone marrow and blood during progression to dysplasia. MSC-derived CAFs that are recruited to the dysplastic stomach express IL-6, Wnt5? and BMP4 and show DNA hypomethylation. Bone marrow (BM)-derived CAFs strongly promote tumor growth in organotypic and xenograft models. In addition, CAFs are generated from MSCs and are recruited to distant tumor sites in a TGF-?- and SDF-1?-dependent manner. Carcinogenesis therefore involves the expansion and relocation of normal bone marrow niche cells to the tumor site where they create a new niche to sustain cancer progression. Since resident (non-BM-derived) CAFs could not be cultured and directly compared to BM-derived CAFs, we additionally isolated total RFP(+) gastric CAFs from aSMA-RFP mice with Helicobacter felis-induced dysplasia, and compared them to GFP(+) BM-derived gastric CAFs from mice with H. felis-induced dysplasia mice that had been transplanted with UBC-EGFP bone marrow. The RFP+ CAFs (HF CAF) represent total CAFs (of which only 20% were BM-derived), while the latter represented only BM-derived CAFs (BM CAF). We compared their gene expression using the Illumina array (MouseWG-6v2) directly after FACS sorting. Interestingly, the GFP+ BM-derived CAFs expressed higher levels of inflammatory genes (IL-6, IL-1?, IL-33) and a number of tumor and stem cell associated factors (CCL5, SPP1, Notch3, MMP9, CD47, CXCR4, PARP10,) compared to the total (RFP+) population of gastric CAFs. Comparison of bone marrow-derived GFP-labeled gastric CAFs versus all gastric CAFs.
2010-10-01 | E-GEOD-23548 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that resists current treatments. To test epigenetic therapy against this cancer we used the DNA demethylating drug 5-aza-2’-deoxycytidine (DAC) in a KrasLSL-G12D; p53LSL-R270H/+; Pdx1-cre; Brca1flex2/flex2 (KPC-Brca1) mouse model of aggressive stroma-rich PDAC. In untreated tumors, we found globally decreased 5-methyl-cytosine (5mC) in malignant epithelial cells and in cancer-associated myofibroblasts (CAFs), and increased amounts of 5-hydroxymethyl-cytosine (5HmC) in CAFs, in progression from pancreatic intraepithelial neoplasia (PanIN) to PDAC. DAC further reduced DNA methylation and slowed PDAC progression, markedly extending survival in an early treatment protocol and significantly though transiently inhibiting tumor growth when initiated later, without adverse side effects. Escaping tumors contained areas of sarcomatoid transformation with disappearance of CAFs. Mixing-allografting experiments and proliferation indices showed that DAC efficacy was due to inhibition of both the malignant epithelial cells and the stromal CAFs. Expression profiling and immunohistochemistry highlighted DAC-induction of STAT1 in the tumors, and DAC plus gamma-interferon produced an additive anti-proliferative effect on PDAC cells. DAC induced strong expression of the testis antigen DAZL in CAFs. These data show that DAC is effective against PDAC in vivo and provide a rationale for future studies combining hypomethylating agents with cytokines and immunotherapy. Treatment of a short-term explant culture of cancer-associated fibroblasts (CAFs) from a KPC-Brca1 mouse pancreatic carcinoma, with 2 micromolar 5-aza-dC (decitabine; DAC) for 48 hours. The experiment includes 3 replicate plates untreated and 3 replicates treated.
2013-01-01 | E-GEOD-42364 | biostudies-arrayexpress
Project description:Prostate cancer (PCa) remains the malignancy with the highest morbidity in men (1). Although early-stage PCa usually causes no symptoms, cancer cells in prostate glands readily metastasize to bones, lymph nodes, lungs, and liver during PCa progression (2). Common strategies, including surgery, radiation therapy, and androgen-deprivation therapy, are promising treatments for early-stage PCa. However, advanced PCa still lacks effective therapeutic strategies (3-5). Thus, researchers are currently focused on inhibiting tumor progression to explore effective therapeutic strategies for PCa treatment (6, 7). Cancer-associated fibroblasts (CAFs), stromal cells derived from normal fibroblasts or epithelia, are one of the major cellular components in the tumor microenvironment (8, 9). Compared with normal fibroblasts, CAFs are activated with increased expression of key protein markers, such as α-SMA, FAP, vimentin and S100A4 protein (10, 11). In the tumor microenvironment, CAFs secrete various growth effectors or cytokines to the extracellular matrix and thereby promote tumor progression by directly enhancing cancer cell growth, angiogenic induction, the extracellular matrix modification, and tumor-promoting inflammatory mediation (11-14). Notably, CAFs could act as an immunosuppressive mediator for the formation of an immunosuppressive tumor environment by recruiting and activating multiple immune cells (15). As such, CAFs might be a potential target in anti-tumor immunotherapy (16, 17). Currently, increased research has focused on inhibiting the immunosuppressive function of prostate cancer-associated fibroblasts (prostate CAFs), which may suggest therapeutic strategies for PCa (18, 19). Polysaccharides from Lentinus edodes are known to exhibit potent anti-tumor and immunomodulatory functions. The anti-tumor mechanisms of L. edodes polysaccharides include regulating the innate immune system by mediating CAF function, preventing tumorigenesis, or directly killing tumor cells via cell cycle regulation or apoptotic induction (20-22). Our previous studies isolated a novel polysaccharide component (MPSSS) from L. edodes. We found the secretome of prostate CAFs treated with MPSSS could inhibit the proliferation of CD4+ and CD8+ T cells, which suggested that MPSSS could prevent the immunosuppressive function of prostate CAFs (22). However, although the secretome of MPSSS-treated prostate CAFs inhibit the proliferation of T cells, how the secretome of MPSSS-treated prostate CAFs affect PCa progression is still unclear. The secretome defines as all proteins secreted by the organism or living cells into the extracellular space, which consists of soluble proteins and extracellular vesicles (EVs) (23). The secretome of prostate CAFs pays vital roles in PCa tumor origination, progression (24, 25). Since EVs contains various molecules (proteins, RNA, DNA and lipid) (26), we speculate that soluble proteins and EVs of prostate CAFs might have the different influence on PCa cells. In this study, the secretome of prostate CAFs untreated/treated with MPSSS were separated into the high molecular weight secretome (>100 kD) and the low molecular weight secretome (3-100 kD) using 100 kD and 3kD MWCO memberane filtration to narrow down the range of active components. The high molecular weight secretome contained extracellular vesicles (EVs) and large soluble proteins, while the low molecular weight secretome contained the small soluble proteins. The secretome of prostate CAFs untreated/treated with MPSSS were used to explore the underlying function and molecular mechanism using quantitative proteomics and multiple biochemical approaches.
2021-03-22 | PXD023689 | Pride