Patterns of alternative splicing of fibronectin pre-mRNA in human adult and fetal tissues

Oyama, Fumitaka; Murata, Yoshiharu; Suganuma, Nobuhiko; Kimura, Toshio; Titani, Koiti; Sekiguchi, Kiyotoshi

doi:10.1021/bi00429a072

Cited by 95 publications

(70 citation statements)

References 43 publications

(46 reference statements)

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“…FN is the most well-studied matrix protein, and it is known that in transformed cells and in malignancies, the splicing pattern of FN pre-mRNA becomes altered, leading to an increased expression of oncofoetal isoforms (93)(94)(95). The ED-A (59) and ED-B (96)(97)(98) are well-known oncofetal isoforms of FN.…”

Section: Discussionmentioning

confidence: 99%

Tumor-Conditioned Macrophages Secrete Migration-Stimulating Factor: A New Marker for M2-Polarization, Influencing Tumor Cell Motility

Solinas

Schiarea

Liguori

et al. 2010

The Journal of Immunology

343

292

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Tumor-associated macrophages (TAMs) are key orchestrators of the tumor microenvironment directly affecting neoplastic cell growth, neoangiogenesis, and extracellular matrix remodeling. In turn, the tumor milieu strongly influences maturation of TAMs and shapes several of their features. To address the early macrophage (Mϕ) differentiation phase in a malignant context, we mimicked a tumor microenvironment by in vitro coculturing human blood monocytes with conditioned media from different cancer cell lines. Only 2 out of 16 tumor cell lines induced Mϕ differentiation due to secreted M-CSF isoforms, including high molecular mass species. A global gene profiling of tumor-conditioned Mϕ was performed. Comparison with other datasets (polarized M1-Mϕ, M2-Mϕ, and TAMs isolated from human tumors) highlighted the upregulation of several genes also shared by TAM and M2-polarized Mϕ. The most expressed genes were selenoprotein 1, osteoactivin, osteopontin, and, interestingly, migration-stimulating factor (MSF), a poorly studied oncofoetal isoform of fibronectin. MSF (present in fetal/cancer epithelial and stromal cells but not in healthy tissues) was never identified in Mϕ. MSF production was confirmed by immunohistochemistry in human TAMs. MSF was induced by M-CSF, IL-4, and TGFβ but not by proinflammatory stimuli. RNA and protein analysis clearly demonstrated that it is specifically associated with the M2 polarization of Mϕ. Tumor-conditioned Mϕ-derived MSFs strongly stimulated tumor cell migration, thus contributing to the motile phenotype of neoplastic cells. In conclusion, MSF is a new molecule associated with the M2 polarization of Mϕ and expressed by TAMs. Its biological function may contribute to Mϕ-mediated promotion of cancer cell invasion and metastasis.

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Section: Discussionmentioning

confidence: 99%

Tumor-Conditioned Macrophages Secrete Migration-Stimulating Factor: A New Marker for M2-Polarization, Influencing Tumor Cell Motility

Solinas

Schiarea

Liguori

et al. 2010

The Journal of Immunology

343

292

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“…During normal physiology, fibronectin isoforms, including extra domain A (ED-A) and extra domain B (ED-B) regions, are expressed at low levels; however, pathological conditions can significantly up-regulate isoforms containing these domains. As such, invasive tumors are well known to express isoforms containing ED-A and ED-B domains (Oyama et al 1989;Midulla et al 2000;Castellani et al 2002;Mhawech et al 2005). A unique truncated isoform of fibronectin has also been shown to be produced by /IL-8 CXCR1, 2 CXCL1/MIP-2 CXCR1, 2 CCL22 CCR4 CCL12 CXCR4, CXCL12, CCR2 IL-10 IL-10R1, 2 S100A8/9 CD36, LTB4 S100A4 S100A4R, HSPG, annexin II Proteases MMP-1,2,3,9,11,14 uPA embryonic fibroblasts and CAFs and is capable of inducing both tumor and fibroblast cell migration (Schor et al 2003).…”

Section: Predominant Residents: Fibroblasts Help Make the Movementioning

confidence: 99%

Migratory neighbors and distant invaders: tumor-associated niche cells

Wels

Kaplan²,

Rafii³

et al. 2008

Genes Dev.

356

302

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The cancer environment is comprised of tumor cells as well as a wide network of stromal and vascular cells participating in the cellular and molecular events necessary for invasion and metastasis. Tumor secretory factors can activate the migration of host cells, both near to and far from the primary tumor site, as well as promote the exodus of cells to distant tissues. Thus, the migration of stromal cells and tumor cells among specialized microenvironments takes place throughout tumor and metastatic progression, providing evidence for the systemic nature of a malignancy. Investigations of the tumor-stromal and stromal-stromal cross-talk involved in cellular migration in cancer may lead to the design of novel therapeutic strategies.Understanding the complex biological networks at play in metastasis requires a precise detailing of the molecular and cellular pathways involved in local and systemic migration. The long prevailing model of invasion and metastasis has focused on the adhesive and migratory capabilities that are intrinsic to tumor cells (Hanahan and Weinberg 2000). Meanwhile, we are becoming increasingly aware that tumors are composed of genetically altered malignant cells along with a heterogeneous population of stromal cells, whose dynamic interactions can profoundly enhance tumor progression and metastasis. Through the production of chemokines, growth factors, and matrix-degrading enzymes (Table 1), supportive cells-including fibroblasts, immune cells, and bone marrow (BM)-derived stem and progenitor cells-support blood vessel formation, break down basement membrane barriers, and attract tumor cells to distant sites. Tumor cells are constantly giving instructions, not only by direct cell-cell interactions, but also by secreted factors that "activate" normal host cells at both proximal and distal sites to migrate, eventually developing permissive niches that, in return, promote tumor cell survival and proliferation. The focus of this review is on the cellular constituents of the primary and metastatic tumor microenvironments, with emphasis on their migratory pathways. We hope to convey that the tumor and host cell interaction is truly reciprocal; while host cells may support tumor cells, tumor cells in turn modulate the microenvironments within which they reside. Furthermore, we highlight that cancer is a systemic disease, encompassing collective cell movements of tumor and stromal cells that are a prerequisite for tumor cell invasion and metastasis. Intrinsic tumor cell migratory capabilitiesInherent to the metastatic process is the capability of tumor cells to migrate through connective tissue barriers comprising cell-cell adherent junctions, basement membranes, and interstitial tissue stroma. This intrinsic migratory behavior is highly dependent on the interplay between adhesive and proteolytic activities. Tumor cell down-regulation of proteins mediating cell-cell interactions, such as cadherins, leads to changes in cell signaling, actin-based cytoskeletal structure, and eventual dissociation from n...

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“…16,17 Loss of E-cadherin expression occurs in malignancies and is associated with poor prognosis in cancer. 18 Increased expression of fibroblast markers including fibronectin, and an alternatively spliced form of fibronectin (ED-A isoform), 19 and fibroblast-specific protein-1 (FSP-1) occur in EMT. FSP-1 in particular has been considered to be a highly specific marker for fibroblasts.…”

mentioning

confidence: 99%

“…13,29 TGF-␤1 in turn can induce the expression of alternatively spliced fibronectin extra type III domain A (FN-ED-A) and other extracellular matrix proteins. 19 Under mechanical stress, FN-ED-A and TGF-␤1 induce an extracellular matrix synthetic phenotype. 30 In this study, we investigated the hypothesis that EMT contributes to gingival overgrowth by assessing for loss of epithelial cell markers and gain of fibroblastic markers in the epithelium and the gain of markers of fibrosis in the connective tissue stroma in human tissue samples in vivo.…”

mentioning

confidence: 99%

Epithelial to Mesenchymal Transition in Gingival Overgrowth

Sume

Kantarcı

Lee

et al. 2010

The American Journal of Pathology

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Epithelial to mesenchymal transition (EMT) occurs normally in development. In pathology, EMT drives cancer and fibrosis. Medication with phenytoin, nifedipine, and cyclosporine-A often causes gingival overgrowth. Based partly on the histopathology of gingival overgrowth, the present study investigates the hypothesis that EMT could contribute to its development. We found that phenytoin-induced human gingival overgrowth tissues, the most fibrotic drug-induced variety, contain diminished epithelial E-cadherin expression, whereas fibroblast-specific protein-1 (FSP-1) and ␣v␤6 integrin levels are up-regulated. In connective tissue stroma, fibronectin and alternatively spliced fibronectin extra type III domain A (FN-ED-A) levels are increased in overgrowth lesions. Transforming growth factor (TGF)-␤1 treatment of primary human gingival epithelial cells cultured in transwell plates resulted in inhibited barrier function as determined by reduced electrical resistance, paracellular permeability assays, and cell surface E-cadherin expression. Moreover , TGF-␤1 altered the expression of other markers of EMT determined at the mRNA and protein levels: E-cadherin decreased, whereas SLUG, fibronectin, matrix metalloproteinase (MMP)2, MMP9, and MMP13 increased. Nifedipine-and cyclosporine A-induced gingival overgrowth tissues similarly contain diminished E-cadherin and elevated levels of FSP-1 and fibronectin, but normal levels of ␣v␤6 integrin. In summary, data in vitro support that human gingival epithelial cells undergo functional and gene expression changes consistent with EMT in response to TGF-␤1, and in vivo studies show that important EMT markers occur in clinical gingival overgrowth tissues. These findings support the hypothesis that EMT likely occurs in drug-induced gingival overgrowth.

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Patterns of alternative splicing of fibronectin pre-mRNA in human adult and fetal tissues

Cited by 95 publications

References 43 publications

Tumor-Conditioned Macrophages Secrete Migration-Stimulating Factor: A New Marker for M2-Polarization, Influencing Tumor Cell Motility

Tumor-Conditioned Macrophages Secrete Migration-Stimulating Factor: A New Marker for M2-Polarization, Influencing Tumor Cell Motility

Migratory neighbors and distant invaders: tumor-associated niche cells

Epithelial to Mesenchymal Transition in Gingival Overgrowth

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