Mesenchymal Stem Cell Targeting of Microscopic Tumors and Tumor Stroma Development Monitored by Noninvasive <i>In vivo</i> Positron Emission Tomography Imaging

Hung, Shih Chieh; Deng, Win Ping; Yang, Wei‐Pang; Liu, Ru‐Shi; Lee, Chien Chih; Su, Tzu Chi; Lin, Ruey‐Jen; Yang, Da; Chang, Chi Wei; Chen, Wei Hong; Wei, Hong-Jian; Gelovani, Juri G.

doi:10.1158/1078-0432.ccr-05-0876

Cited by 264 publications

(210 citation statements)

References 42 publications

(29 reference statements)

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“…MSCs are by definition the precursors of fibroblasts. Their contribution to generating tumor stroma (Hung et al, 2005;Wolf et al, 2005), especially its reactive subpopulations (Direkze et al, 2004), has already been suggested; so they could be candidates for the tumorpromoting or tumorigenic phenotypical changes that a neoplastic microenvironment induces in the stromal population.…”

Section: Phenotype Convergence Between Msc and Mts M Galiè Et Almentioning

confidence: 99%

Mesenchymal stem cells share molecular signature with mesenchymal tumor cells and favor early tumor growth in syngeneic mice

et al. 2007

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Tumor microenvironment in carcinomas recruits mesenchymal cells with an abnormal proangiogenic and invasive phenotype. It is not clear whether mesenchymal tumor cells (MTCs) derive from the activation of mature fibroblasts or from their stem cell precursors. However, stromal cell activation in tumors resembles in several aspects the mesenchymal rearrangement which normally occurs during reparative processes such as wound healing. Mesenchymal stem cells (MSCs) play a crucial role in developmental and reparative processes and have extraordinary proangiogenic potential, on the basis of which they are thought to show great promise for the treatment of ischemic disorders. Here, we show that MTCs have proangiogenic potential and that they share the transcriptional expression of the best-known proangiogenic factors with MSCs. We also found that MTCs and MSCs have the same molecular signature for stemness-related genes, and that when co-implanted with cancer cells in syngeneic animals MSCs determine early tumor appearance, probably by favoring the angiogenic switch. Our data (1) reveal crucial aspects of the proangiogenic phenotype of MTCs, (2) strongly suggest their stem origin and (3) signal the risk of therapeutic use of MSCs in tumorpromoting conditions.

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Section: Phenotype Convergence Between Msc and Mts M Galiè Et Almentioning

confidence: 99%

Mesenchymal stem cells share molecular signature with mesenchymal tumor cells and favor early tumor growth in syngeneic mice

et al. 2007

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“…MSCs have been shown to contribute to the formation of fibrous scars after injury [9]. Systemically transferred MSCs have been described to migrate into colon carcinomas [10]. In the setting of wound healing, MSCs can act as immunoregulatory cells by releasing IL-10 and prostaglandin E2, or by expressing the enzyme indoleamine 2, 3-dioxygenase (IDO) [11][12][13].…”

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confidence: 99%

Human mesenchymal stem cells respond to native but not oxidized damage associated molecular pattern molecules from necrotic (tumor) material

et al. 2011

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Necrosis is a characteristic feature of advanced solid tumors. Released necrotic factors, also referred to as damage associated molecular patterns (DAMPs), are known to critically impact the tumor microenvironment by enhancing angiogenesis or influencing the immune response. We have recently shown that DAMPs can act as chemoattractants and activators of granulocytes. We demonstrate that necrotic material from both normal and tumor cells promotes proliferation and trafficking of human mesenchymal stem cells (MSCs). We characterize the protein high mobility group box 1 (HMGB1) as a crucial member of DAMPs within necrotic material. In addition, we show that DAMPs interfere with expression of indoleamine 2, 3-dioxygenase (IDO) in MSCs. The biological activity of necrotic material toward MSCs is abolished once these DAMPs are oxidized. MSCs found within tumor tissue can act as immunoregulatory cells and are able to promote tumor metastasis, thus playing a crucial role within the tumor microenvironment. Here, we reveal DAMPs to be crucial factors in the setting of MSC biology within the tumor microenvironment. The tumor microenvironment is characterized by reducing and hypoxic conditions that protect DAMPs from oxidation. Based on our results, oxidizing conditions should be considered for therapeutic approaches that target the tumor microenvironment.Key words: Chemotaxis . Damage associated molecular patterns . Mesenchymal stem cells . Proliferation . Supporting Information available online See accompanying Commentary by Pistoia and Raffaghello IntroductionRegardless of the origin and site of neoplastic cells, necrotic cell death is a characteristic feature of advanced solid tumor mainly due to three conditions: (i) inadequate nutrition supply to tumor cells as a consequence of imbalance between tumor growth and angiogenesis, (ii) the host's cytotoxic immune response to the tumor, and (iii) downregulation of programmed (apoptotic) cell death by the tumor itself. Released factors following necrotic cell death are also referred to as damage associated molecular patterns (DAMPs). DAMPs can critically impact the tumor microenvironment by enhancing angiogenesis or influencing [5,6]. MSCs are pluripotent progenitor cells that contribute to the maintenance and regeneration of a variety of connective tissues, including bone, adipose, cartilage, and muscle [7]. Although MSCs reside predominantly in the bone marrow, they are also distributed throughout many other tissues, where they are thought to serve as local sources of dormant stem cells [8]. The contributions of MSCs to tissue formation become apparent in cases of tissue remodelling after injury or chronic inflammation. These conditions are typically accompanied by mobilization of multipotent MSCs from bone marrow and their subsequent recruitment to the site of damage [8]. MSCs have been shown to contribute to the formation of fibrous scars after injury [9]. Systemically transferred MSCs have been described to migrate into colon carcinomas [10]. In the setting of wound he...

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“…It has been well demonstrated that MSCs are recruited to the site of tumor,9, 11, 12, 13, 14 playing a pivotal role by interfering with other immune cells present in the surrounding tumor tissue. For this reason, it is highly relevant to determine how MSCs exert their immunoregulatory functions.…”

Section: Discussionmentioning

confidence: 99%

ATP promotes immunosuppressive capacities of mesenchymal stromal cells by enhancing the expression of indoleamine dioxygenase

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et al. 2018

Immunity Inflam & Disease

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IntroductionMSCs are often found within tumors, promote cancer progression and enhance metastasis. MSCs can act as immuosuppressive cells, partially due to the expression of the enzyme indoleamine dioxygenase (IDO) which converts tryptophan to kynurenine. Decreased concentration of tryptophan and increased kynurenine, both interfere with effective immune response. Damage associated molecular patterns (DAMPs) including ATP are found within the tumor microenvironment, attract MSCs, and influence their biology.MethodsBone marrow derived MSCs were exposed to ATP for 4 days, in the presence of 100 ng IFNγ/mL. Intracellular expression of IDO in MSCs was assessed by FACS. Conditioned media from thus stimulated MSCs was analyzed for kynurenine content and its suppressive effect on lymphocyte proliferation. Apyrase or P2 × 7‐receptor antagonist (AZ 11645373) were applied in order to inhibit ATP induced effect on MSCs.ResultsWe demonstrate, that ATP at concentrations between 0.062 and 0.5 mM increases dose dependently the expression of IDO in MSCs with subsequent increased kynurenine concentrations within the supernatant at about 60%. This effect could be abolished completely in the presence of ATP degrading enzyme (apyrase) or when MSCs were pretreated with a P2 × 7‐receptor antagonist (AZ 11645373). Consistently, supernatants from MSCs stimulated with ATP, inhibited lymphocyte proliferation from 65% to 16%.ConclusionsWe characterized ATP as a DAMP family member responsible for necrosis‐induced immunomodulation. Given the increased concentration of DAMPs within tumor tissue and the fact that DAMPs can act as chemotattractants to MSCs, our results have implications for therapeutic strategies targeting the tumor microenvironment.

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Mesenchymal Stem Cell Targeting of Microscopic Tumors and Tumor Stroma Development Monitored by Noninvasive In vivo Positron Emission Tomography Imaging

Abstract: The aim of this study was to assess the efficacy human mesenchymal stem cells (

Cited by 264 publications

References 42 publications

Mesenchymal stem cells share molecular signature with mesenchymal tumor cells and favor early tumor growth in syngeneic mice

Mesenchymal stem cells share molecular signature with mesenchymal tumor cells and favor early tumor growth in syngeneic mice

Human mesenchymal stem cells respond to native but not oxidized damage associated molecular pattern molecules from necrotic (tumor) material

ATP promotes immunosuppressive capacities of mesenchymal stromal cells by enhancing the expression of indoleamine dioxygenase

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