IL-3 is a novel target to interfere with tumor vasculature

Dentelli, Patrizia; Rosso, Arturo; Olgasi, Cristina; Camussi, Giovanni; Brizzi, Maria Felice

doi:10.1038/onc.2011.204

Cited by 49 publications

(45 citation statements)

References 44 publications

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“…ASC proliferation Cell proliferation was assayed at different time intervals by direct cell count or FACS analysis (FACSCalibur flow cytometer; BD Biosciences, San Jose, CA, USA) using the proliferating cell nuclear antigen (PCNA) antibody [30]. Alternatively, cell proliferation was performed at day16 after 48 h apocynin treatment or p47 phox silencing on HG-cultured N-ASCs [31].…”

Section: Methodsmentioning

confidence: 99%

A diabetic milieu promotes OCT4 and NANOG production in human visceral-derived adipose stem cells

et al. 2012

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Aims/hypothesis Successful outcomes have been obtained by exploiting adipose-derived stem cells (ASCs) in regenerative medicine. NADPH oxidase (NOX)-generated reactive oxygen species (ROS) are known to control stem cell self-renewal. Several high glucose (HG)-mediated effects depend on NOX-generated ROS. In this study, we investigated whether, and how mechanistically, HG concentrations control ASC fate in patients with diabetes. Methods ASCs from the visceral adipose tissue of nondiabetic (N-ASCs) and diabetic participants (D-ASCs), identified by surface markers, were counted and evaluated for ROS generation and stem cell properties. Their ability to release soluble factors was assessed by BioPlex analysis. To reproduce an invitro diabetic glucose milieu, N-ASCs were cultured in HG (25 mmol/l) or normal glucose (NG) concentration (5 mmol/l), as control. ASC pluripotency was assessed by in vitro study. The p47 phox NOX subunit, AKT and octamer-binding transcription factor 4 (OCT4; also known as POU5F1) were knocked down by small-interfering RNA technology. Stem-cell features were evaluated by sphere cluster formation. Results The ASC number was higher in diabetic patients than in non-diabetic controls. Production of OCT4 and NANOG, stem-cell-specific transcription factors, was upregulated in D-ASCs compared with N-ASCs. Moreover, we found that ROS production and AKT activation drove D-ASC, but not N-ASC, secretion. When N-ASCs were cultured in vitro in the presence of HG, they also expressed OCT4/NANOG and formed spheres. By knock-down of the p47 phox NOX subunit, AKT and OCT4 we demonstrated that NOX-generated ROS and their downstream signals are crucial for HG-mediated ASC de-differentiation and proinflammatory cytokine production. Conclusions/interpretation We herein provide a rationale for exploiting D-ASCs in regenerative medicine and/or exploiting HG preconditioning to increase ASCs ex vivo.

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Section: Methodsmentioning

confidence: 99%

A diabetic milieu promotes OCT4 and NANOG production in human visceral-derived adipose stem cells

et al. 2012

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“…Tumors are known to produce the whole spectrum of colony-stimulating factors (IL-3, G-CSF, and GM-CSF) (64–66, 75) that potentially influence proliferation of progenitor cells, neutrophil release from BM, and prolongation of their lifespan in tissues. Other sources of G-CSF are endothelial cells (76) and neutrophils themselves (34).…”

Section: Type I Ifns Influence the Turnover And The Lifespan Of Neutrmentioning

confidence: 99%

The Essential Role of Type I Interferons in Differentiation and Activation of Tumor-Associated Neutrophils

2016

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Type I interferons (IFNs) were first characterized in the process of viral interference. However, since then, IFNs are found to be involved in a wide range of biological processes. In the mouse, type I IFNs comprise a large family of cytokines. At least 12 IFN-α and one IFN-β can be found and they all signal through the same receptor (IFNAR). A hierarchy of expression has been established for type I IFNs, where IFN-β is induced first and it activates in a paracrine and autocrine fashion a cascade of other type I IFNs. Besides its importance in the induction of the IFN cascade, IFN-β is also constitutively expressed in low amounts under normal non-inflammatory conditions, thus facilitating “primed” state of the immune system. In the context of cancer, type I IFNs show strong antitumor function as they play a key role in mounting antitumor immune responses through the modulation of neutrophil differentiation, activation, and migration. Owing to their plasticity, neutrophils play diverse roles during cancer development and metastasis since they possess both tumor-promoting (N2) and tumor-limiting (N1) properties. Notably, the differentiation into antitumor phenotype is strongly supported by type I IFNs. It could also be shown that these cytokines are critical for the suppression of neutrophil migration into tumor and metastasis site by regulating chemokine receptors, e.g., CXCR2 on these cells and by influencing their longevity. Type I IFNs limit the life span of neutrophils by influencing both, the extrinsic as well as the intrinsic apoptosis pathways. Such antitumor neutrophils efficiently suppress the pro-angiogenic factors expression, e.g., vascular endothelial growth factor and matrix metallopeptidase 9. This in turn restricts tumor vascularization and growth. Thus, type I IFNs appear to be the part of the natural tumor surveillance mechanism. Here we provide an up to date review of how type I IFNs influence the pro- and antitumor properties of neutrophils. Understanding these mechanisms is particularly important from a therapeutic point of view.

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“…In the present study, we showed that the expression of c-Kit increased in the c-Kit + ASCs/4T1 coculture group compared with single cultures and that the proliferation of breast cancer cells was enhanced by c-Kit + ASCs after coculture. Moreover, the release of membrane-bound KitL, as an adhesion/survival-promoting molecule for stem cells, depends on IL-3 [34]. IL-3 acts as a nonspecific proinflammatory cytokine and drives cell proliferation by the JAK/STAT and PI3K/AKT pathways [35–37].…”

Section: Discussionmentioning

confidence: 99%

c-Kit-Positive Adipose Tissue-Derived Mesenchymal Stem Cells Promote the Growth and Angiogenesis of Breast Cancer

Cheng

2017

BioMed Research International

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Background Adipose tissue-derived mesenchymal stem cells (ASCs) improve the regenerative ability and retention of fat grafts for breast reconstruction in cancer patients following mastectomy. However, ASCs have also been shown to promote breast cancer cell growth and metastasis. For the safety of ASC application, we aimed to identify specific markers for the subpopulation of ASCs that enhance the growth of breast cancer. Methods ASCs and bone marrow-derived vascular endothelial progenitor cells (EPCs) were isolated from Balb/c mice. c-Kit-positive (c-Kit+) or c-Kit-negative (c-Kit−) ASCs were cocultured with 4T1 breast cancer cells. Orthotropic murine models of 4T1, EPCs + 4T1, and c-Kit+/-ASCs + 4T1/EPCs were established in Balb/c mice. Results In coculture, c-Kit+ ASCs enhanced the viability and proliferation of 4T1 cells and stimulated c-Kit expression and interleukin-3 (IL-3) release. In mouse models, c-Kit+ASCs + 4T1/EPCs coinjection increased the tumor volume and vessel formation. Moreover, IL-3, stromal cell-derived factor-1, and vascular endothelial growth factor A in the c-Kit+ASCs + 4T1/EPCs coinjection group were higher than those in the 4T1, EPCs + 4T1, and c-Kit−ASCs + 4T1/EPCs groups. Conclusions c-Kit+ ASCs may promote breast cancer growth and angiogenesis by a synergistic effect of c-Kit and IL-3. Our findings suggest that c-Kit+ subpopulations of ASCs should be eliminated in fat grafts for breast reconstruction of cancer patients following mastectomy.

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IL-3 is a novel target to interfere with tumor vasculature

Cited by 49 publications

References 44 publications

A diabetic milieu promotes OCT4 and NANOG production in human visceral-derived adipose stem cells

A diabetic milieu promotes OCT4 and NANOG production in human visceral-derived adipose stem cells

The Essential Role of Type I Interferons in Differentiation and Activation of Tumor-Associated Neutrophils

c-Kit-Positive Adipose Tissue-Derived Mesenchymal Stem Cells Promote the Growth and Angiogenesis of Breast Cancer

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