Role of Tumor Associated Fibroblasts in Human Liver Regeneration, Cirrhosis, and Cancer

Cesselli, Daniela; Beltrami, Antonio Paolo; Poz, Alessandra; Marzinotto, Stefania; Comisso, Elisa; Bergamin, Natascha; Bourkoula, Evgenia; Pucer, Anja; Puppato, Elisa; Toffoletto, Barbara; Sorrentino, Marisa; Baccarani, Umberto; Avellini, Claudio; Beltrami, Carlo Alberto

doi:10.4061/2011/120925

Cited by 24 publications

(33 citation statements)

References 44 publications

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“…The origin of the myofibroblasts and CAFs might be derived from the epithelial mesenchymal transition (EMT), resident fibroblasts, or bone marrow derived stem cells. It has been demonstrated that multipotent adult stem cells with CAFs properties was found not only in HCC, but also in cirrhotic liver, supporting the evidence that the CAFs could be originated from resident progenitor cells [27]. …”

Section: Discussionmentioning

confidence: 81%

The Expression of CD90/Thy-1 in Hepatocellular Carcinoma: An In Vivo and In Vitro Study

et al. 2013

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Although the CD90 (Thy-1) was proposed as biomarker of several tumors and cancer stem cells, the involvement of this molecule in the progression of hepatocellular carcinoma (HCC) and other less frequent hepatic neoplasms is still undefined. The distribution of CD90 was investigated both in in vivo (human tissues samples) and in vitro (human HCC cell line JHH-6). A total of 67 liver tumors were analyzed: 51 HCC, 6 cholangiocarcinoma and 10 hepatoblastoma. In all cases, paired tissue sample of both the tumor and cirrhotic liver was available. Hepatic tissue obtained in 12 healthy livers was used as control. CD90 gene expression was studied by RT-qPCR, protein expression was assessed by quantitative Western Blot, immunofluorescence and flow cytometry. The CD90 expression analysis showed a significant increment in tumor compared to both its paired cirrhotic tissue and normal liver (p<0.05 and p<0.001, respectively). This increase was accompanied by the up-regulation of stromal component in the cancer, as demonstrated by alpha smooth muscle actin staining. In vitro analysis of JHH-6 cell line showed a higher proliferation capacity of CD90+ compared to CD90- cells (p<0.001), also noticed in 3D clonogenic assay (p<0.05), associated by a significant higher expression of the promoting factors (hepatocyte growth factor, fibroblast associated protein and alpha smooth muscle actin 2). A higher expression of the breast cancer resistance protein was found in CD90+ subpopulation while the multidrug resistance protein 1 showed an opposite behavior. Collectively, these results point to the importance of CD90 in the HCC.

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Section: Discussionmentioning

confidence: 81%

The Expression of CD90/Thy-1 in Hepatocellular Carcinoma: An In Vivo and In Vitro Study

et al. 2013

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“…Cells from glioma were isolated and cultured applying, with minor modifications, previously described protocols . Briefly, glioma fragments were mechanically enzymatically dissociated and cells less than 40 µm in diameter were cultured in expansion medium as in . See Supporting Information methods for details.…”

Section: Methodsmentioning

confidence: 99%

“…After enzymatic detachment, cells were incubated with properly conjugated or unconjugated antibodies. The analysis was performed either by FACS‐Calibur, FACScanto (BD Biosciences, San Jose, CA, http://www.bdbiosciences.com), or by CyAn (Beckman Coulter s.r.l., Milan, Italy, https://www.beckmancoulter.com) . Exosome staining was performed after incubation of exosomes with 4 µm aldehyde/sulfate latex beads (Molecular Probes, Invitrogen, Carlsbad CA, http://www.lifetechnologies.com).…”

Section: Methodsmentioning

confidence: 99%

Glioma‐Associated Stem Cells: A Novel Class of Tumor‐Supporting Cells Able to Predict Prognosis of Human Low‐Grade Gliomas

et al. 2014

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Background: Translational medicine aims at transferring advances in basic science research into new approaches for diagnosis and treatment of diseases. Low-grade gliomas (LGG) have a heterogeneous clinical behavior that can be only partially predicted employing current state-of-theart markers, hindering the decision-making process. To deepen our comprehension on tumor heterogeneity, we dissected the mechanism of interaction between tumor cells and relevant components of the neoplastic environment, isolating, from LGG and high-grade gliomas (HGG), proliferating stem cell lines from both the glioma stroma and, where possible, the neoplasm. Methods and Findings: We isolated glioma-associated stem cells (GASC) from LGG (n540) and HGG (n573). GASC showed stem cell features, anchorage-independent growth, and supported the malignant properties of both A172 cells and human glioma-stem cells, mainly through the release of exosomes. Finally, starting from GASC obtained from HGG (n513) and LGG (n512) we defined a score, based on the expression of 9 GASC surface markers, whose prognostic value was assayed on 40 subsequent LGG-patients. At the multivariate Cox analysis, the GASCbased score was the only independent predictor of overall survival and malignant progression free-survival. Conclusions: The microenvironment of both LGG and HGG hosts non-tumorigenic multipotent stem cells that can increase in vitro the biological aggressiveness of gliomainitiating cells through the release of exosomes. The clinical importance of this finding is supported by the strong prognostic value associated with the characteristics of GASC. This patientbased approach can provide a groundbreaking method to predict prognosis and to exploit novel strategies that target the tumor stroma.

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“…This was demonstrated after implantation of integrin α11-deficient fibroblasts and NSCLC cells in SCID mice caused reduction of tumor volume, which was restored upon re-expression of α11 in knock-out mouse embryonic fibroblasts. Similarly, a population of CAFs from hepatocellular carcinoma liver tissue demonstrated significantly higher surface expression of integrin α4 and lower expression of α2 when compared to nonneoplastic tissue [165]. CAFs express several alpha subunits, including αV and α5, which interact with multiple beta subunits, and are capable of binding collagen, fibronectin, and soluble factors such as TGF-β1 [166–168].…”

Section: Transmembrane Proteinsmentioning

confidence: 99%

Insidious Changes in Stromal Matrix Fuel Cancer Progression

Miles

Sikes

2014

Molecular Cancer Research

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Reciprocal interactions between tumor and stromal cells propel cancer progression and metastasis. An understanding of the complex contributions of the tumor stroma to cancer progression necessitates a careful examination of the extracellular matrix (ECM), which is largely synthesized and modulated by Cancer Associated Fibroblasts (CAFs). This structurally supportive meshwork serves as a signaling scaffold for a myriad of biological processes and responses favoring tumor progression. The ECM is a repository for growth factors and cytokines that promote tumor growth, proliferation, and metastasis through diverse interactions with soluble and insoluble ECM components. Growth factors activated by proteases are involved in the initiation of cell signaling pathways essential to invasion and survival. Various transmembrane proteins produced by the cancer stroma bind the collagen and fibronectin-rich matrix to induce proliferation, adhesion and migration of cancer cells, as well as protease activation. Integrins are critical liaisons between tumor cells and the surrounding stroma, and with their mechano-sensing ability induce cell signaling pathways associated with contractility and migration. Proteoglycans also bind and interact with various matrix proteins in the tumor microenvironment to promote cancer progression. Together, these components function to mediate crosstalk between tumor cells and fibroblasts ultimately to promote tumor survival and metastasis. These stromal factors, which may be expressed differentially according to cancer stage, have prognostic utility and potential. In this review, we examine changes in the ECM of cancer associated fibroblasts induced through carcinogenesis, and the implications of these changes on cancer progression.

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Role of Tumor Associated Fibroblasts in Human Liver Regeneration, Cirrhosis, and Cancer

Cited by 24 publications

References 44 publications

The Expression of CD90/Thy-1 in Hepatocellular Carcinoma: An In Vivo and In Vitro Study

The Expression of CD90/Thy-1 in Hepatocellular Carcinoma: An In Vivo and In Vitro Study

Glioma‐Associated Stem Cells: A Novel Class of Tumor‐Supporting Cells Able to Predict Prognosis of Human Low‐Grade Gliomas

Insidious Changes in Stromal Matrix Fuel Cancer Progression

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