Cancer-Associated Fibroblasts Drive the Progression of Metastasis through both Paracrine and Mechanical Pressure on Cancer Tissue

Karagiannis, George S.; Poutahidis, Theofilos; Erdman, Susan E.; Kirsch, Richard; Riddell, Robert H.; Diamandis, Eleftherios P.

doi:10.1158/1541-7786.mcr-12-0307

Cited by 447 publications

(370 citation statements)

References 132 publications

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“…49 The tumor stroma consists of the extracellular matrix (ECM) and cellular components. In the tumor microenvironment, tumor-infiltrating immunosuppressive cells, including Treg cells, MDSCs, alternatively activated macrophages (M2), and immature/tolerogenic DC, inhibit anticancer immunity and play a role in tumor angiogenesis and cancer cell survival, proliferation, and metastatic potential.…”

Section: Discussionmentioning

confidence: 99%

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

OuYang

et al. 2015

OncoImmunology

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Keywords: COX-2, myeloid-derived suppressor cells, nasopharyngeal carcinomaAbbreviations: ARG-1, arginase 1; COX-2, cyclooxygenase-2; DFS, disease-free survival; EMT, epithelial-mesenchymal transition; GM-CSF, granulocyte-monocyte-colony stimulating factor; iNOS, inducible nitric oxide synthase; LNMMA, L-NG-monomethylarginine; MDSCs, myeloid-derived suppressor cells; NAC, N-acetylcysteine; NOHA, N-hydroxy-nor-L-arginine; NOX2, NADPH oxidase; NPC, nasopharyngeal carcinoma; ROS, reactive oxygen species; siRNA, small interfering RNA; TCF4, T-cell factor 4; TGF, transforming growth factor b; T-MDSCs, tumor-induced MDSCs; VEGF, vascular endothelial growth factorThe expansion of myeloid-derived suppressor cells (MDSCs) is a common feature of cancer, but its biological roles and molecular mechanism remain unclear. Here, we investigated a molecular link between MDSC expansion and tumor cell metastasis in nasopharyngeal carcinoma (NPC). We demonstrated that MDSCs expanded and were positively correlated with the elevated tumor COX-2 expression and serum IL-6 levels in NPC patients. Importantly, COX-2 and MDSCs were poor predictors of patient disease-free survival (DFS). Knocking down tumor COX-2 expression hampered functional TW03-mediated-MDSC cell (T-MDSC) induction with IL-6 blocking. We identified that T-MDSCs promoted NPC cell migration and invasion by triggering the epithelial-mesenchymal transition (EMT) on cell-to-cell contact, and TMDSCs enhanced tumor experimental lung metastasis in vivo. Interestingly, the contact between T-MDSCs and NPC cells enhanced tumor COX-2 expression, which subsequently activated the b-catenin/TCF4 pathway, resulting in EMT of the cancer cells. Blocking transforming growth factor b (TGFb) or inducible nitric oxide synthase (iNOS) significantly abolished the T-MDSC-induced upregulation of COX-2 and EMT scores in NPC cells, whereas the administration of TGFb or L-arginine supplements upregulated COX-2 expression and EMT scores in NPC cells. These findings reveal that COX-2 is a key factor mediating the interaction between MDSCs and tumor cells, suggesting that the inhibition of COX-2 or MDSCs has the potential to suppress NPC metastasis.

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Section: Discussionmentioning

confidence: 99%

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

OuYang

et al. 2015

OncoImmunology

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“…Infiltration of the tumor by different host cell types, leading to an evolving stromal compartment intermingled with tumor cells, is required to create a permissive environment for the invasion of (epi)genetically altered tumor cells (1,2 ). The tumor infiltrate is composed of a variety of leukocyte subtypes (immune and inflammatory cells), blood endothelial cells (BECs), 2 and lymphatic endothelial cells (LECs), leading to the (lymph)angiogenic switch, carcinoma-associated fibroblasts (CAFs), and bone marrow-derived mesenchymal stem cells (MSCs) that contribute to quantitative and qualitative changes in the extracellular matrix (ECM) (3,4 ). Desmoplasia, the fibrotic stromal reaction associated with most carcinomas, is characterized by the local deposition of different fibrillar collagen types and often correlates with adverse prognosis in carcinomas (4,5 ).…”

confidence: 99%

Targeting the Tumor Microenvironment for Cancer Therapy

2013

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BACKGROUND With the emergence of the tumor microenvironment as an essential ingredient of cancer malignancy, therapies targeting the host compartment of tumors have begun to be designed and applied in the clinic. CONTENT The malignant features of cancer cells cannot be manifested without an important interplay between cancer cells and their local environment. The tumor infiltrate composed of immune cells, angiogenic vascular cells, lymphatic endothelial cells, and cancer-associated fibroblastic cells contributes actively to cancer progression. The ability to change these surroundings is an important property by which tumor cells are able to acquire some of the hallmark functions necessary for tumor growth and metastatic dissemination. Thus in the clinical setting the targeting of the tumor microenvironment to encapsulate or destroy cancer cells in their local environment has become mandatory. The variety of stromal cells, the complexity of the molecular components of the tumor stroma, and the similarity with normal tissue present huge challenges for therapies targeting the tumor microenvironment. These issues and their interplay are addressed in this review. After a decade of intensive clinical trials targeting cellular components of the tumor microenvironment, more recent investigations have shed light on the important role in cancer progression played by the noncellular stromal compartment composed of the extracellular matrix. SUMMARY A better understanding of how the tumor environment affects cancer progression should provide new targets for the isolation and destruction of cancer cells via interference with the complex crosstalk established between cancer cells, host cells, and their surrounding extracellular matrix.

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“…The activated myofibroblasts accompanying tumors known as cancer‐associated fibroblasts (CAFs) belong to the principal constituents of the tumor stroma, playing important role in the tumor microenvironment 29. The CAFs were shown to mediate cancer‐related inflammation by expressing proinflammatory and tumor‐promoting factors and promotion of the cancer cell invasion and ECM remodeling 30, 31.…”

Section: Introductionmentioning

confidence: 99%

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

et al. 2018

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BackgroundMajor human gastrointestinal pathogen Helicobacter pylori (H. pylori) colonizes the gastric mucosa causing inflammation and severe complications including cancer, but the involvement of fibroblasts in the pathogenesis of these disorders in H. pylori‐infected stomach has been little studied. Normal stroma contains few fibroblasts, especially myofibroblasts. Their number rapidly increases in the reactive stroma surrounding inflammatory region and neoplastic tissue; however, the interaction between H. pylori and fibroblasts remains unknown. We determined the effect of coincubation of normal rat gastric fibroblasts with alive H. pylori (cagA+vacA+) and H. pylori (cagA−vacA−) strains on the differentiation of these fibroblasts into cells possessing characteristics of cancer‐associated fibroblasts (CAFs) able to induce epithelial‐mesenchymal transition (EMT) of normal rat gastric epithelial cells (RGM‐1).Materials and MethodsThe panel of CAFs markers mRNA was analyzed in H. pylori (cagA+vacA+)‐infected fibroblasts by RT‐PCR. After insert coculture of differentiated fibroblasts with RGM‐1 cells from 24 up to 48, 72, and 96 hours, the mRNA expression for EMT‐associated genes was analyzed by RT‐PCR.ResultsThe mRNA expression for CAFs markers was significantly increased after 72 hours of infection with H. pylori (cagA+vacA+) but not H. pylori (cagA−vacA−) strain. Following coculture with CAFs, RGM‐1 cells showed significant decrease in E‐cadherin mRNA, and the parallel increase in the expression of Twist and Snail transcription factors mRNA was observed along with the overexpression of mRNAs for TGFβR, HGFR, FGFR, N‐cadherin, vimentin, α‐SMA, VEGF, and integrin‐β1.Conclusion Helicobacter pylori (cagA+vacA+) strain induces differentiation of normal fibroblasts into CAFs, likely to initiate the EMT process in RGM‐1 epithelial cell line.

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Cancer-Associated Fibroblasts Drive the Progression of Metastasis through both Paracrine and Mechanical Pressure on Cancer Tissue

Cited by 447 publications

References 132 publications

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

Targeting the Tumor Microenvironment for Cancer Therapy

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

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