Publications by authors named "Luisa Ottobrini"

35 Publications

Imaging Metformin Efficacy as Add-On Therapy in Cells and Mouse Models of Human EGFR Glioblastoma.

Front Oncol 2021 3;11:664149. Epub 2021 May 3.

Department of Medicine and Surgery and Tecnomed Foundation, University of Milano - Bicocca, Monza, Italy.

Glioblastoma (GBM) is a highly aggressive tumor of the brain. Despite the efforts, response to current therapies is poor and 2-years survival rate ranging from 6-12%. Here, we evaluated the preclinical efficacy of Metformin (MET) as add-on therapy to Temozolomide (TMZ) and the ability of [F]FLT (activity of thymidine kinase 1 related to cell proliferation) and [F]VC701 (translocator protein, TSPO) Positron Emission Tomography (PET) radiotracers to predict tumor response to therapy. Indeed, TSPO is expressed on the outer mitochondrial membrane of activated microglia/macrophages, tumor cells, astrocytes and endothelial cells. TMZ-sensitive (Gli36ΔEGFR-1 and L0627) or -resistant (Gli36ΔEGFR-2) GBM cell lines representative of classical molecular subtype were tested and in orthotopic mouse models. Our results indicate that , MET increased the efficacy of TMZ on TMZ-sensitive and on TMZ-resistant cells by deregulating the balance between pro-survival () and pro-apoptotic () Bcl-family members and promoting early apoptosis in both Gli36ΔEGFR-1 and Gli36ΔEGFR-2 cells. , MET add-on significantly extended the median survival of tumor-bearing mice compared to TMZ-treated ones and reduced the rate of recurrence in the TMZ-sensitive models. PET studies with the cell proliferation radiopharmaceutical [F]FLT performed at early time during treatment were able to distinguish responder from non-responder to TMZ but not to predict the duration of the effect. On the contrary, [F]VC701 uptake was reduced only in mice treated with MET plus TMZ and levels of uptake negatively correlated with animals' survival. Overall, our data showed that MET addition improved TMZ efficacy in GBM preclinical models representative of classical molecular subtype increasing survival time and reducing tumor relapsing rate. Finally, results from PET imaging suggest that the reduction of cell proliferation represents a common mechanism of TMZ and combined treatment, whereas only the last was able to reduce TSPO. This reduction was associated with the duration of treatment response. TSPO-ligand may be used as a complementary molecular imaging marker to predict tumor microenvironment related treatment effects.
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http://dx.doi.org/10.3389/fonc.2021.664149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126706PMC
May 2021

Placental Antioxidant Defenses and Autophagy-Related Genes in Maternal Obesity and Gestational Diabetes Mellitus.

Nutrients 2021 Apr 15;13(4). Epub 2021 Apr 15.

Department of Biomedical and Clinical Sciences "Luigi Sacco", Università degli Studi di Milano, 20157 Milano, Italy.

Maternal obesity and gestational diabetes mellitus (GDM) are increasing worldwide, representing risk factors for both mother and child short/long-term outcomes. Oxidative stress, lipotoxicity and altered autophagy have already been reported in obesity, but few studies have focused on obese pregnant women with GDM. Antioxidant and macro/chaperone-mediated autophagy (CMA)-related gene expressions were evaluated herein in obese and GDM placentas. A total of 47 women with singleton pregnancies delivered by elective cesarean section were enrolled: 16 normal weight (NW), 18 obese with no comorbidities (OB GDM(-)), 13 obese with GDM (OB GDM(+)). Placental gene expression was assessed by real-time PCR. Antioxidant gene expression (, , ) decreased, the pro-autophagic gene increased and the chaperone-mediated autophagy regulator decreased in OB GDM(-) vs. NW. On the other hand, expression increased in OB GDM(+) vs. OB GDM(-). When analyzing results in relation to fetal sex, we found sexual dimorphism for both antioxidant and CMA-related gene expressions. These preliminary results can pave the way for further analyses aimed at elucidating the placental autophagy role in metabolic pregnancy disorders and its potential targetability for the treatment of diabetes outcomes.
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http://dx.doi.org/10.3390/nu13041303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071310PMC
April 2021

Triple negative aggressive phenotype controlled by miR-135b and miR-365: new theranostics candidates.

Sci Rep 2021 Mar 22;11(1):6553. Epub 2021 Mar 22.

Institute of Molecular Bioimaging and Physiology, National Research Council (IBFM-CNR), Via F.Cervi 93, 20090, Segrate-Milan, Milan, Italy.

Triple negative breast cancer (TNBC) accounts for about a fifth of all breast cancers and includes a diverse group of cancers. The heterogeneity of TNBC and the lack of target receptors on the cell surface make it difficult to develop specific therapeutic treatments. These aspects cause the high negative prognosis of patients with this type of tumor. The analysis of the molecular profiles of TNBC samples has allowed a better characterization of this tumor, supporting the search for new reliable diagnostic markers. To this end, we have developed a bioinformatic approach to integrate networks of genes differentially expressed in basal breast cancer compared to healthy tissues, with miRNAs able to regulate their expression. We studied the role of these miRNAs in TNBC subtype cell lines. We therefore identified two miRNAs, namely miR-135b and miR-365, with a central role in regulating the altered functional pathways in basal breast cancer. These two miRNAs are differentially expressed in human TNBC immunohistochemistry-selected tissues, and their modulation has been shown to play a role in the proliferation of tumor control and its migratory and invasive capacity in TNBC subtype cell lines. From the perspective of personalized medicine, we managed to modulate the expression of the two miRNAs in organotypic cultures, suggesting their possible use as diagnostic and therapeutic molecules. miR-135b and miR-365 have a key role in TNBC, controlling proliferation and invasion. Their detection could be helpful in TNBC diagnosis, while their modulation could become a new therapeutic tool for TNBC.
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http://dx.doi.org/10.1038/s41598-021-85746-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985188PMC
March 2021

The Multifaceted Role of CMA in Glioma: Enemy or Ally?

Int J Mol Sci 2021 Feb 23;22(4). Epub 2021 Feb 23.

Department of Pathophysiology and Transplantation, University of Milan, Via F.Cervi 93, Segrate, 20090 Milan, Italy.

Chaperone-mediated autophagy (CMA) is a catabolic pathway fundamental for cell homeostasis, by which specific damaged or non-essential proteins are degraded. CMA activity has three main levels of regulation. The first regulatory level is based on the targetability of specific proteins possessing a KFERQ-like domain, which can be recognized by specific chaperones and delivered to the lysosomes. Target protein unfolding and translocation into the lysosomal lumen constitutes the second level of CMA regulation and is based on the modulation of Lamp2A multimerization. Finally, the activity of some accessory proteins represents the third regulatory level of CMA activity. CMA's role in oncology has not been fully clarified covering both pro-survival and pro-death roles in different contexts. Taking all this into account, it is possible to comprehend the actual complexity of both CMA regulation and the cellular consequences of its activity allowing it to be elected as a modulatory and not only catabolic machinery. In this review, the role covered by CMA in oncology is discussed with a focus on its relevance in glioma. Molecular correlates of CMA importance in glioma responsiveness to treatment are described to identify new early efficacy biomarkers and new therapeutic targets to overcome resistance.
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http://dx.doi.org/10.3390/ijms22042217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926390PMC
February 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Theranostic application of in HER2+ breast cancer.

Theranostics 2020 1;10(1):50-61. Epub 2020 Jan 1.

Institute of Molecular Bioimaging and Physiology, National Research Council (IBFM-CNR), Via F.Cervi 93, 20090 Segrate-Milan, Milan, Italy.

Human epidermal growth factor receptor 2 (HER2) is overexpressed/amplified in one third of breast cancers (BCs), and is associated with the poorer prognosis and the higher metastatic potential in BC. Emerging evidences highlight the role of microRNAs (miRNAs) in the regulation of several cellular processes, including BC.

Methods: Here we identified, by approach, a group of three miRNAs with central biological role (high degree centrality) in HER2+ BC. We validated their dysregulation in HER2+ BC and we analysed their functional role by approaches on selected cell lines and by experiments in an animal model.

Results: We found that their expression is dysregulated in both HER2+ BC cell lines and human samples. Focusing our study on the only upregulated miRNA, , we discovered that it acts as an oncogene and its upregulation is required for HER2+ cell proliferation. It controls the metastatic potential of HER2+ BC subtype by regulating migration and invasion of the cell.

Conclusions: In HER2+ BC oncogenic is able to regulate HIF1α pathway by directly targeting VHL mRNA, a molecule important for the degradation of HIF1α. The overexpression of , observed in HER2+ BC, causes increased proliferation and migration of the BC cells. More important, silencing succeeds in delaying tumor growth, thus could be proposed as a therapeutic probe in HER2+ BC tumors.
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http://dx.doi.org/10.7150/thno.36274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929607PMC
April 2021

Intracellular Redox-Balance Involvement in Temozolomide Resistance-Related Molecular Mechanisms in Glioblastoma.

Cells 2019 10 24;8(11). Epub 2019 Oct 24.

Department of Pathophysiology and Transplantation, University of Milan, 20090 Segrate (MI), Italy.

Glioblastoma (GBM) is the most common astrocytic-derived brain tumor in adults, characterized by a poor prognosis mainly due to the resistance to the available therapy. The study of mitochondria-derived oxidative stress, and of the biological events that orbit around it, might help in the comprehension of the molecular mechanisms at the base of GBM responsiveness to Temozolomide (TMZ). Sensitive and resistant GBM cells were used to test the role of mitochondrial ROS release in TMZ-resistance. Chaperone-Mediated Autophagy (CMA) activation in relation to reactive oxygen species (ROS) release has been measured by monitoring the expression of specific genes. Treatments with HO were used to test their potential in reverting resistance. Fluctuations of cytoplasmic ROS levels were accountable for CMA induction and cytotoxic effects observed in TMZ sensitive cells after treatment. On the other hand, in resistant cells, TMZ failed in producing an increase in cytoplasmic ROS levels and CMA activation, preventing GBM cell toxicity. By increasing oxidative stress, CMA activation was recovered, as also cell cytotoxicity, especially in combination with TMZ treatment. Herein, for the first time, it is shown the relation between mitochondrial ROS release, CMA activation and TMZ-responsiveness in GBM.
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http://dx.doi.org/10.3390/cells8111315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912456PMC
October 2019

Role of Metformin and AKT Axis Modulation in the Reversion of Hypoxia Induced TMZ-Resistance in Glioma Cells.

Front Oncol 2019 31;9:463. Epub 2019 May 31.

Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Segrate, Italy.

Hypoxia is a key driver of tumor adaptation promoting tumor progression and resistance to therapy. Hypoxia related pathways might represent attractive targets for the treatment of Glioblastoma Multiforme (GBM), that up to date is characterized by a poor prognosis. Primary aim of this study was to investigate the role of hypoxia and hypoxia-related modifications in the effect of temozolomide (TMZ) given alone or in association with the antidiabetic agent Metformin (MET) or the PI3K/mTOR blocker, BEZ235. The study was conducted in the TMZ responsive U251 and resistant T98 GBM cells. Our results showed that during hypoxia, TMZ plus MET reduced viability of U251 cells affecting also CD133 and CD90 expressing cells. This effect was associated with a reduction of HIF-1α activity, VEGF release and AKT activation. In T98 TMZ-resistant cells, TMZ plus MET exerted similar effects on HIF-1α. However, in this cell line, TMZ plus MET failed to reduce CD133 positive cells and AKT phosphorylation. Nevertheless, the administration of the dual PI3K/mTOR inhibitor BEZ235 potentiated the effect of TMZ plus MET on cell viability, inducing a pro-apoptotic phenotype during hypoxic condition also in T98 cells, suggesting the block of the PI3K/AKT/mTOR pathway as a complementary target to further overcome GBM resistance during hypoxia. In conclusion, we proposed TMZ plus MET as suitable treatment to revert TMZ-resistance also during hypoxia, an effect potentiated by the inhibition of PI3K/mTOR axis.
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http://dx.doi.org/10.3389/fonc.2019.00463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554426PMC
May 2019

Specific V-ATPase expression sub-classifies IDHwt lower-grade gliomas and impacts glioma growth in vivo.

EBioMedicine 2019 Mar 5;41:214-224. Epub 2019 Feb 5.

Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; Fondazione Istituto Nazionale Genetica Molecolare 'Romeo ed Enrica Invernizzi', Milan, Italy. Electronic address:

Background: Cancer cells use specific V-ATPase subunits to activate oncogenic pathways. Therefore, we investigated V-ATPase deregulation in aggressive gliomas and associated signaling.

Methods: V-ATPase genes expression and associated pathways were analyzed in different series of glioma available from public databases, as well as in patients' cohort. Activation of pathways was analyzed at gene and protein expression levels. A genetic model of glioma in Drosophila melanogaster and mice with GBM patients-derived orthotopic xenografts were used as in vivo models of disease.

Findings: GBM and recurrent gliomas display a specific V-ATPase signature. Such signature resolves the heterogeneous class of IDH-wild type lower-grade gliomas, identifying the patients with worse prognosis independently from clinical and molecular features (p = 0·03, by Cox proportional-hazards model). In vivo, V-ATPase subunits deregulation significantly impacts tumor growth and proliferation. At the molecular level, GBM-like V-ATPase expression correlates with upregulation of Homeobox genes.

Interpretation: Our data identify a V-ATPase signature that accompanies glioma aggressiveness and suggest new entry points for glioma stratification and follow-up. FUND: This work was supported by Fondazione Cariplo (2014-1148 to VV), Fondazione IRCCS Ca' Granda, and Fondazione INGM Grant in Molecular Medicine 2014 (to VV).
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http://dx.doi.org/10.1016/j.ebiom.2019.01.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441867PMC
March 2019

A GBM-like V-ATPase signature directs cell-cell tumor signaling and reprogramming via large oncosomes.

EBioMedicine 2019 Mar 6;41:225-235. Epub 2019 Feb 6.

Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; Fondazione Istituto Nazionale Genetica Molecolare 'Romeo ed Enrica Invernizzi', Milan, Italy. Electronic address:

Background: The V-ATPase proton pump controls acidification of intra and extra-cellular milieu in both physiological and pathological conditions. We previously showed that some V-ATPase subunits are enriched in glioma stem cells and in patients with poor survival. In this study, we investigated how expression of a GBM-like V-ATPase pump influences the non-neoplastic brain microenvironment.

Methods: Large oncosome (LO) vesicles were isolated from primary glioblastoma (GBM) neurospheres, or from patient sera, and co-cultured with primary neoplastic or non-neoplastic brain cells. LO transcript and protein contents were analyzed by qPCR, immunoblotting and immunogold staining. Activation of pathways in recipient cells was determined at gene and protein expression levels. V-ATPase activity was impaired by Bafilomycin A1 or gene silencing.

Findings: GBM neurospheres influence their non-neoplastic microenvironment by delivering the V-ATPase subunit V1G1 and the homeobox genes HOXA7, HOXA10, and POU3F2 to recipient cells via LO. LOs reprogram recipient cells to proliferate, grow as spheres and to migrate. Moreover, LOs are particularly abundant in the circulation of GBM patients with short survival time. Finally, impairment of V-ATPase reduces LOs activity.

Interpretation: We identified a novel mechanism adopted by glioma stem cells to promote disease progression via LO-mediated reprogramming of their microenvironment. Our data provide preliminary evidence for future development of LO-based liquid biopsies and suggest a novel potential strategy to contrast glioma progression. FUND: This work was supported by Fondazione Cariplo (2014-1148 to VV) and by the Italian Minister of Health-Ricerca Corrente program 2017 (to SF).
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http://dx.doi.org/10.1016/j.ebiom.2019.01.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441844PMC
March 2019

Hypoxia-Inducible Factor-1α Activity as a Switch for Glioblastoma Responsiveness to Temozolomide.

Front Oncol 2018 2;8:249. Epub 2018 Jul 2.

Institute of Molecular Bioimaging and Physiology (IBFM), CNR, Milan, Italy.

Rationale: The activity of the transcription factor, hypoxia-inducible factor (HIF)-1α, is a common driver of a number of the pathways involved in the aggressiveness of glioblastomas (GBMs), and it has been suggested that the reduction in this activity observed, soon after the administration of temozolomide (TMZ), can be a biomarker of an early response in GBM models. As HIF-1α is a tightly regulated protein, studying the processes involved in its downregulation could shed new light on the mechanisms underlying GBM sensitivity or resistance to TMZ.

Methods: The effect of HIF-1α silencing on cell responsiveness to TMZ was assessed in four genetically different human GBM cell lines by evaluating cell viability and apoptosis-related gene balance. LAMP-2A silencing was used to evaluate the contribution of chaperone-mediated autophagy (CMA) to the modulation of HIF-1α activity in TMZ-sensitive and TMZ-resistant cells.

Results: The results showed that HIF-1α but not HIF-2α activity is associated with GBM responsiveness to TMZ: its downregulation improves the response of TMZ-resistant cells, while blocking CMA-mediated HIF-1α degradation induces resistance to TMZ in TMZ-sensitive cells. These findings are in line with the modulation of crucial apoptosis-related genes.

Conclusion: Our results demonstrate the central role played by HIF-1α activity in determining the sensitivity or resistance of GBMs to TMZ, and we suggest that CMA is the cellular mechanism responsible for modulating this activity after TMZ treatment.
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http://dx.doi.org/10.3389/fonc.2018.00249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036118PMC
July 2018

Transcriptional activity of oestrogen receptors in the course of embryo development.

J Endocrinol 2018 09;238(3):165-176

Center of Excellence on Neurodegenerative DiseasesUniversity of Milan, Milan, Italy

Oestrogens are well-known proliferation and differentiation factors that play an essential role in the correct development of sex-related organs and behaviour in mammals. With the use of the ERE-Luc reporter mouse model, we show herein that throughout mouse development, oestrogen receptors (ERs) are active starting from day 12 post conception. Most interestingly, we show that prenatal luciferase expression in each organ is proportionally different in relation to the germ layer of the origin. The luciferase content is highest in ectoderm-derived organs (such as brain and skin) and is lowest in endoderm-derived organs (such as liver, lung, thymus and intestine). Consistent with the testosterone surge occurring in male mice at the end of pregnancy, in the first 2 days after birth, we observed a significant increase in the luciferase content in several organs, including the liver, bone, gonads and hindbrain. The results of the present study show a widespread transcriptional activity of ERs in developing embryos, pointing to the potential contribution of these receptors in the development of non-reproductive as well as reproductive organs. Consequently, the findings reported here might be relevant in explaining the significant differences in male and female physiopathology reported by a growing number of studies and may underline the necessity for more systematic analyses aimed at the identification of the prenatal effects of drugs interfering with ER signalling, such as aromatase inhibitors or endocrine disrupter chemicals.
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http://dx.doi.org/10.1530/JOE-18-0003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084787PMC
September 2018

Short-Term Fasting Reveals Amino Acid Metabolism as a Major Sex-Discriminating Factor in the Liver.

Cell Metab 2018 08 14;28(2):256-267.e5. Epub 2018 Jun 14.

Center of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy; Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, Milan 20133, Italy. Electronic address:

Sex impacts on liver physiology with severe consequences for energy metabolism and response to xenobiotic, hepatic, and extra-hepatic diseases. The comprehension of the biology subtending sex-related hepatic differences is therefore very relevant in the medical, pharmacological, and dietary perspective. The extensive application of metabolomics paired to transcriptomics here shows that, in the case of short-term fasting, the decision to maintain lipid synthesis using amino acids (aa) as a source of fuel is the key discriminant for the hepatic metabolism of male and female mice. Pharmacological and genetic interventions indicate that the hepatic estrogen receptor (ERα) has a key role in this sex-related strategy that is primed around birth by the aromatase-dependent conversion of testosterone into estradiol. This energy partition strategy, possibly the result of an evolutionary pressure enabling mammals to tailor their reproductive capacities to nutritional status, is most important to direct future sex-specific dietary and medical interventions.
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http://dx.doi.org/10.1016/j.cmet.2018.05.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084280PMC
August 2018

Nitric Oxide Generated by Tumor-Associated Macrophages Is Responsible for Cancer Resistance to Cisplatin and Correlated With Syntaxin 4 and Acid Sphingomyelinase Inhibition.

Front Immunol 2018 29;9:1186. Epub 2018 May 29.

"Eugenio Medea" Scientific Institute, Bosisio Parini, Italy.

Tumor microenvironment is fundamental for cancer progression and chemoresistance. Among stromal cells tumor-associated macrophages (TAMs) represent the largest population of infiltrating inflammatory cells in malignant tumors, promoting their growth, invasion, and immune evasion. M2-polarized TAMs are endowed with the nitric oxide (NO)-generating enzyme inducible nitric oxide synthase (iNOS). NO has divergent effects on tumors, since it can either stimulate tumor cells growth or promote their death depending on the source of it; likewise the role of iNOS in cancer differs depending on the cell type. The role of NO generated by TAMs has not been investigated. Using different tumor models and we found that NO generated by iNOS of M2-polarized TAMs is able to protect tumor cells from apoptosis induced by the chemotherapeutic agent cisplatin (CDDP). Here, we demonstrate that the protective effect of NO depends on the inhibition of acid sphingomyelinase (A-SMase), which is activated by CDDP in a pathway involving the death receptor CD95. Mechanistic insights indicate that NO actions occur generation of cyclic GMP and activation of protein kinase G (PKG), inducing phosphorylation of syntaxin 4 (synt4), a SNARE protein responsible for A-SMase trafficking and activation. Noteworthy, phosphorylation of synt4 at serine 78 by PKG is responsible for the proteasome-dependent degradation of synt4, which limits the CDDP-induced exposure of A-SMase to the plasma membrane of tumor cells. This inhibits the cytotoxic mechanism of CDDP reducing A-SMase-triggered apoptosis. This is the first demonstration that endogenous NO system is a key mechanism through which TAMs protect tumor cells from chemotherapeutic drug-induced apoptosis. The identification of the pathway responsible for A-SMase activity downregulation in tumors leading to chemoresistance warrants further investigations as a means to identify new anti-cancer molecules capable of specifically inhibiting synt4 degradation.
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http://dx.doi.org/10.3389/fimmu.2018.01186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987706PMC
August 2019

Exploring the potential of polyurethane-based soft foam as cell-free scaffold for soft tissue regeneration.

Acta Biomater 2018 06 12;73:141-153. Epub 2018 Apr 12.

Fondazione Filarete, Viale Ortles 22/4, 20139 Milan, Italy; CIMAINA, Dipartimento di Fisica, Università degli Studi di Milano, Via Celoria 16, 20133 Milan, Italy.

Reconstructive treatment after trauma and tumor resection would greatly benefit from an effective soft tissue regeneration. The use of cell-free scaffolds for adipose tissue regeneration in vivo is emerging as an attractive alternative to tissue-engineered constructs, since this approach avoids complications due to cell manipulation and lack of synchronous vascularization. In this study, we developed a biodegradable polyurethane-based scaffold for soft tissue regeneration, characterized by an exceptional combination between softness and resilience. Exploring the potential as a cell-free scaffold required profound understanding of the impact of its intrinsic physico-chemical properties on the biological performance in vivo. We investigated the effect of the scaffold's hydrophilic character, degradation kinetics, and internal morphology on (i) the local inflammatory response and activation of MGCs (foreign body response); (ii) its ability to promote rapid vascularisation, cell infiltration and migration through the scaffold over time; and (iii) the grade of maturation of the newly formed tissue into vascularized soft tissue in a murine model. The study revealed that soft tissue regeneration in vivo proceeded by gradual infiltration of undifferentiated mesenchymal cells though the periphery toward the center of the scaffold, where the rapid formation of a functional and well-formed vascular network supported cell viability overtime.

Statement Of Significance: Exploring the potential of polyurethane-based soft foam as cell-free scaffold for soft tissue regeneration. In this work, we address the unmet need for synthetic functional soft tissue substitutes that provide adequate biological and mechanical support to soft tissue. We developed a series of flexible cross-linked polyurethane copolymer scaffolds with remarkable fatigue-resistance and tunable physico-chemical properties for soft tissue regeneration in vivo. Accordingly, we could extend the potential of this class of biomaterials, which was so far confined for bone and osteochondral tissue regeneration, to other types of connective tissue.
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http://dx.doi.org/10.1016/j.actbio.2018.04.011DOI Listing
June 2018

Metformin and temozolomide, a synergic option to overcome resistance in glioblastoma multiforme models.

Oncotarget 2017 12 6;8(68):113090-113104. Epub 2017 Dec 6.

Tecnomed Foundation and Medicine and Surgery Department, University of Milan-Bicocca, Monza, Italy.

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with poor survival. Cytoreduction in association with radiotherapy and temozolomide (TMZ) is the standard therapy, but response is heterogeneous and life expectancy is limited. The combined use of chemotherapeutic agents with drugs targeting cell metabolism is becoming an interesting therapeutic option for cancer treatment. Here, we found that metformin (MET) enhances TMZ effect on TMZ-sensitive cell line (U251) and overcomes TMZ-resistance in T98G GBM cell line. In particular, combined-treatment modulated apoptosis by increasing Bax/Bcl-2 ratio, and reduced Reactive Oxygen Species (ROS) production. We also observed that MET associated with TMZ was able to reduce the expression of glioma stem cells (GSC) marker CD90 particularly in T98G cells but not that of CD133. experiments showed that combined treatment with TMZ and MET significantly slowed down growth of TMZ-resistant tumors but did not affect overall survival of TMZ-sensitive tumor bearing mice. In conclusion, our results showed that metformin is able to enhance TMZ effect in TMZ-resistant cell line suggesting its potential use in TMZ refractory GBM patients. However, the lack of effect on a GBM malignancy marker like CD133 requires further evaluation since it might influence response duration.
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http://dx.doi.org/10.18632/oncotarget.23028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762574PMC
December 2017

Development of clinical simultaneous SPECT/MRI.

Br J Radiol 2018 Jan 7;91(1081):20160690. Epub 2017 Mar 7.

2 Dipartimento di Elettronica Informazione e Bioingegneria, Politecnico di Milano and Instituto Nacionale di Fisica Nucleare (INFN), Milan, Italy.

There is increasing clinical use of combined positron emission tomography and MRI, but to date there has been no clinical system developed capable of simultaneous single-photon emission computed tomography (SPECT) and MRI. There has been development of preclinical systems, but there are several challenges faced by researchers who are developing a clinical prototype including the need for the system to be compact and stationary with MRI-compatible components. The limited work in this area is described with specific reference to the Integrated SPECT/MRI for Enhanced stratification in Radio-chemo Therapy (INSERT) project, which is at an advanced stage of developing a clinical prototype. Issues of SPECT/MRI compatibility are outlined and the clinical appeal of such a system is discussed, especially in the management of brain tumour treatment.
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http://dx.doi.org/10.1259/bjr.20160690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966197PMC
January 2018

MicroRNA-567 dysregulation contributes to carcinogenesis of breast cancer, targeting tumor cell proliferation, and migration.

Breast Cancer Res Treat 2017 02 20;161(3):605-616. Epub 2016 Dec 20.

Institute of Molecular Bioimaging and Physiology, National Research Council (IBFM-CNR), Via F.Cervi 93, 20090, Segrate-Milan, Milan, Italy.

Purpose: We demonstrated that Hsa-miR-567 expression is significantly downregulated in poor prognosis breast cancer, compared to better prognosis breast cancer, having a role in the control of cell proliferation and migration by regulating KPNA4 gene.

Methods And Results: In this study, based on our previously published in silico results, we proved both in vitro (cell line studies) and ex vivo (clinical studies), that Hsa-miR-567 expression is significantly downregulated in breast cancer with poor prognosis when compared to breast cancer with better prognosis. More intriguingly, we demonstrated that the ectopic expression of Hsa-miR-567 in poor prognosis breast cancer cell line strongly inhibits in vitro cell proliferation and migration. Furthermore, we showed in vivo that breast cancer cells, stably expressing Hsa-miR-567, xenografted in mouse, reduce tumor growth ability. Consistently, we found that karyopherin 4 (KPNA4), predicted target gene of Hsa-miR-567 as identified by our in silico analysis, is upregulated in highly aggressive MDA-MB-231 breast cancer cell line and patient tissues with poor prognosis with respect to good prognosis.

Conclusions: Our results suggest a potential role of Hsa-miR-567 as a novel prognostic biomarker for BC and as regulator of KPNA4.
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http://dx.doi.org/10.1007/s10549-016-4079-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241340PMC
February 2017

Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming.

Cancer Cell 2016 08;30(2):257-272

Prostate Cancer Discovery and Development Program, Tumor Microenvironment and Metastasis Program, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA. Electronic address:

Hypoxia is a universal driver of aggressive tumor behavior, but the underlying mechanisms are not completely understood. Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex. In turn, this pathway switches tumor metabolism toward glycolysis, antagonizes apoptosis and autophagy, dampens oxidative stress, and maintains tumor cell proliferation in the face of severe hypoxia. Mitochondrial Akt-PDK1 signaling correlates with unfavorable prognostic markers and shorter survival in glioma patients and may provide an "actionable" therapeutic target in cancer.
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http://dx.doi.org/10.1016/j.ccell.2016.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131882PMC
August 2016

MiR675-5p Acts on HIF-1α to Sustain Hypoxic Responses: A New Therapeutic Strategy for Glioma.

Theranostics 2016 8;6(8):1105-18. Epub 2016 May 8.

6. Dipartimento di Biotecnologie Cellulari ed Ematologia, Sapienza University of Rome, Rome 00185, Italy;

Hypoxia is a common feature in solid tumours. In glioma, it is considered the major driving force for tumour angiogenesis and correlates with enhanced resistance to conventional therapies, increased invasiveness and a poor prognosis for patients. Here we describe, for the first time, that miR675-5p, embedded in hypoxia-induced long non-coding RNA H19, plays a mandatory role in establishing a hypoxic response and in promoting hypoxia-mediated angiogenesis. We demonstrated, in vitro and in vivo, that miR675-5p over expression in normoxia is sufficient to induce a hypoxic moreover, miR675-5p depletion in low oxygen conditions, drastically abolishes hypoxic responses including angiogenesis. In addition, our data indicate an interaction of miR675-5p, HIF-1α mRNA and the RNA Binding Protein HuR in hypoxia-induced responses. We suggest the modulation of miR675-5p as a new therapeutic option to promote or abolish hypoxia induced angiogenesis.
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http://dx.doi.org/10.7150/thno.14700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893639PMC
October 2017

Optical imaging probes in oncology.

Oncotarget 2016 Jul;7(30):48753-48787

Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

Cancer is a complex disease, characterized by alteration of different physiological molecular processes and cellular features. Keeping this in mind, the possibility of early identification and detection of specific tumor biomarkers by non-invasive approaches could improve early diagnosis and patient management.Different molecular imaging procedures provide powerful tools for detection and non-invasive characterization of oncological lesions. Clinical studies are mainly based on the use of computed tomography, nuclear-based imaging techniques and magnetic resonance imaging. Preclinical imaging in small animal models entails the use of dedicated instruments, and beyond the already cited imaging techniques, it includes also optical imaging studies. Optical imaging strategies are based on the use of luminescent or fluorescent reporter genes or injectable fluorescent or luminescent probes that provide the possibility to study tumor features even by means of fluorescence and luminescence imaging. Currently, most of these probes are used only in animal models, but the possibility of applying some of them also in the clinics is under evaluation.The importance of tumor imaging, the ease of use of optical imaging instruments, the commercial availability of a wide range of probes as well as the continuous description of newly developed probes, demonstrate the significance of these applications. The aim of this review is providing a complete description of the possible optical imaging procedures available for the non-invasive assessment of tumor features in oncological murine models. In particular, the characteristics of both commercially available and newly developed probes will be outlined and discussed.
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http://dx.doi.org/10.18632/oncotarget.9066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217050PMC
July 2016

Immunological Characterization of Whole Tumour Lysate-Loaded Dendritic Cells for Cancer Immunotherapy.

PLoS One 2016 21;11(1):e0146622. Epub 2016 Jan 21.

Department of Pathophysiology and Transplantation, University of Milan, Segrate, Milan, Italy.

Introduction: Dendritic cells play a key role as initiators of T-cell responses, and even if tumour antigen-loaded dendritic cells can induce anti-tumour responses, their efficacy has been questioned, suggesting a need to enhance immunization strategies.

Matherials & Methods: We focused on the characterization of bone marrow-derived dendritic cells pulsed with whole tumour lysate (TAA-DC), as a source of known and unknown antigens, in a mouse model of breast cancer (MMTV-Ras). Dendritic cells were evaluated for antigen uptake and for the expression of MHC class I/II and costimulatory molecules and markers associated with maturation.

Results: Results showed that antigen-loaded dendritic cells are characterized by a phenotypically semi-mature/mature profile and by the upregulation of genes involved in antigen presentation and T-cell priming. Activated dendritic cells stimulated T-cell proliferation and induced the production of high concentrations of IL-12p70 and IFN-γ but only low levels of IL-10, indicating their ability to elicit a TH1-immune response. Furthermore, administration of Antigen loaded-Dendritic Cells in MMTV-Ras mice evoked a strong anti-tumour response in vivo as demonstrated by a general activation of immunocompetent cells and the release of TH1 cytokines.

Conclusion: Data herein could be useful in the design of antitumoral DC-based therapies, showing a specific activation of immune system against breast cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146622PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721657PMC
July 2016

In vivo imaging study of angiogenesis in a channelized porous scaffold.

Mol Imaging 2015 ;14

The main scientific issue hindering the development of tissue engineering technologies is the lack of proper vascularization. Among the various approaches developed for boosting vascularization, scaffold design has attracted increasing interest over the last few years. The aim of this article is to illustrate a scaffold design strategy for enhancing vascularization based on sacrificial microfabrication of embedded microchannels. This approach was combined with an innovative poly(ether urethane urea) (PEUtU) porous scaffold to provide an alternative graft substitute material for the treatment of tissue defects. Fluorescent and chemiluminescent imaging combined with computed tomography were used to study the behavior of the scaffold composition within living subjects by analyzing angiogenesis and inflammation processes and observing the variation in x-ray absorption, respectively. For this purpose, an IntegriSense 680 probe was used in vivo for the localization and quantification of integrin αvβ3, due to its critical involvement in angiogenesis, and a XenoLight RediJect Inflammation Probe for the study of the decline in inflammation progression during healing. Overall, the collected data suggest the advantages of embedding a synthetic vascular network into a PEUtU porous matrix to enhance in vivo tissue integration, maturation, and regeneration. Moreover, our imaging approach proved to be an efficient and versatile tool for scaffold in vivo testing.
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http://dx.doi.org/10.2310/7290.2015.00011DOI Listing
March 2016

Exogenous adult postmortem neural precursors attenuate secondary degeneration and promote myelin sparing and functional recovery following experimental spinal cord injury.

Cell Transplant 2015 8;24(4):703-19. Epub 2014 Oct 8.

Laboratory of Pharmacology, Department of Health Sciences, University of Milan, Milan, Italy.

Spinal cord injury (SCI) is a debilitating clinical condition, characterized by a complex of neurological dysfunctions. Neural stem cells from the subventricular zone of the forebrain have been considered a potential tool for cell replacement therapies. We recently isolated a subclass of neural progenitors from the cadaver of mouse donors. These cells, named postmortem neural precursor cells (PM-NPCs), express both erythropoietin (EPO) and its receptor. Their EPO-dependent differentiation abilities produce a significantly higher percentage of neurons than regular NSCs. The cholinergic yield is also higher. The aim of the present study was to evaluate the potential repair properties of PM-NPCs in a mouse model of traumatic SCI. Labeled PM-NPCs were administered intravenously; then the functional recovery and the fate of transplanted cells were studied. Animals transplanted with PM-NPCs showed a remarkable improved recovery of hindlimb function that was evaluated up to 90 days after lesion. This was accompanied by reduced myelin loss, counteraction of the invasion of the lesion site by the inflammatory cells, and an attenuation of secondary degeneration. PM-NPCs migrate mostly at the injury site, where they survive at a significantly higher extent than classical NSCs. These cells accumulate at the edges of the lesion, where a reach neuropile is formed by MAP2- and β-tubulin III-positive transplanted cells that are also mostly labeled by anti-ChAT antibodies.
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http://dx.doi.org/10.3727/096368914X685140DOI Listing
December 2015

Exogenous adult postmortem neural precursors attenuate secondary degeneration and promote myelin sparing and functional recovery following experimental spinal cord injury.

Cell Transplant 2015 8;24(4):703-19. Epub 2014 Oct 8.

Laboratory of Pharmacology, Department of Health Sciences, University of Milan, Milan, Italy.

Spinal cord injury (SCI) is a debilitating clinical condition, characterized by a complex of neurological dysfunctions. Neural stem cells from the subventricular zone of the forebrain have been considered a potential tool for cell replacement therapies. We recently isolated a subclass of neural progenitors from the cadaver of mouse donors. These cells, named postmortem neural precursor cells (PM-NPCs), express both erythropoietin (EPO) and its receptor. Their EPO-dependent differentiation abilities produce a significantly higher percentage of neurons than regular NSCs. The cholinergic yield is also higher. The aim of the present study was to evaluate the potential repair properties of PM-NPCs in a mouse model of traumatic SCI. Labeled PM-NPCs were administered intravenously; then the functional recovery and the fate of transplanted cells were studied. Animals transplanted with PM-NPCs showed a remarkable improved recovery of hindlimb function that was evaluated up to 90 days after lesion. This was accompanied by reduced myelin loss, counteraction of the invasion of the lesion site by the inflammatory cells, and an attenuation of secondary degeneration. PM-NPCs migrate mostly at the injury site, where they survive at a significantly higher extent than classical NSCs. These cells accumulate at the edges of the lesion, where a reach neuropile is formed by MAP2- and β-tubulin III-positive transplanted cells that are also mostly labeled by anti-ChAT antibodies.
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http://dx.doi.org/10.3727/096368914X685140DOI Listing
December 2015

A reliable indirect cell-labelling protocol for optical imaging allows ex vivo visualisation of mesenchymal stem cells after transplantation.

Arch Ital Biol 2013 Sep;151(3):114-25

Department of Neurology and Laboratory of Neuroscience - IRCCS Istituto Auxologico Italiano, via Zucchi 18, 20095 Cusano Milanino, Milan, Italy - Email:

We set out to assess the feasibility of exploiting expression of the mCherry gene, after lentiviral infection, in order visualise bone marrow-derived human mesenchymal stem cells (hMSCs) by optical imaging, and to provide proof of principle of this approach as a method for cell tracking and quantification in pre-clinical models. Commercial hMSCs were infected with a lentiviral vector carrying the mCherry gene under the control of the phosphoglycerate kinase promoter. After extensive in vitro culture, infected hMSCs were analysed for viability, morphology, differentiation capability, and maintenance of fluorescence. Thereafter, mCherry-positive cells were transplanted into unilaterally 6-hydroxy-dopamine lesioned rats (an experimental model of Parkinson's disease). Our analysis showed that hMSCs can be efficiently transduced with the lentiviral vector, retaining their biological features even in the long term. Intrastriatally transplanted mCherry-positive hMSCs can be detected ex vivo by a sensitive cooled CCD camera, both in the whole brain and in serial slices, and relatively quantified. Our protocol was found to be a reliable means of studying the viability of implanted hMSCs. mCherry labelling appears to be readily applicable in the post-transplantation tracking of stem cells and could favour the rapid development of new therapeutic targets for clinical treatments.
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http://dx.doi.org/10.4449/aib.v151i3.1463DOI Listing
September 2013

In vivo imaging of lymph node migration of MNP- and (111)In-labeled dendritic cells in a transgenic mouse model of breast cancer (MMTV-Ras).

Mol Imaging Biol 2012 Apr;14(2):183-96

Department of Biomedical Sciences and Technologies, Section of Radiological Sciences, University of Milan, via di Rudinì 8, 20142 Milan, Italy.

Purpose: The authors present a protocol for the in vivo evaluation, using different imaging techniques, of lymph node (LN) homing of tumor-specific dendritic cells (DCs) in a murine breast cancer model.

Procedures: Bone marrow DCs were labeled with paramagnetic nanoparticles (MNPs) or (111)In-oxine. Antigen loading was performed using tumor lysate. Mature DCs were injected into the footpads of transgenic tumor-bearing mice (MMTV-Ras) and DC migration was tracked by magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT). Ex vivo analyses were performed to validate the imaging data.

Results: DC labeling, both with MNPs and with (111)In-oxine, did not affect DC phenotype or functionality. MRI and SPECT allowed the detection of iron and (111)In in both axillary and popliteal LNs. Immunohistochemistry and γ-counting revealed the presence of DCs in LNs.

Conclusions: MRI and SPECT imaging, by allowing in vivo dynamic monitoring of DC migration, could further the development and optimization of efficient anti-cancer vaccines.
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http://dx.doi.org/10.1007/s11307-011-0496-0DOI Listing
April 2012

Labeling protocols for in vivo tracking of human skeletal muscle cells (HSkMCs) by magnetic resonance and bioluminescence imaging.

Mol Imaging Biol 2012 Feb;14(1):47-59

Department of Biomedical Sciences and Technologies, Section of Radiological Sciences, University of Milan, Via di Rudinì 8, 20142 Milan, Italy.

Purpose: We propose herein labeling protocols for multimodal in vivo visualization of human skeletal muscle cells (HSkMCs) by MRI and BLI to investigate the survival, localization, and proliferation/differentiation of these cells in cell-mediated therapy.

Procedures: HSkMCs were labeled with different quantities of Endorem® and transfection agents or infected with lentiviral vector expressing the luciferase gene under the myogenin promoter. Cells were evaluated before and after intra-arterial injection in NUDE mice with N₂-induced muscle inflammation.

Results: Neither iron labeling nor infection affected cell features; the number of iron-positive cells increased proportionally to the iron content in the medium and in the presence of transfection agents. Loaded cells were detected for up to 1 month by MRI and 2 months by BLI.

Conclusions: These protocols could be used to visualize new stem cells, in vivo and over time, in preclinical studies of cell-based treatments for myopathies of different etiologies.
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http://dx.doi.org/10.1007/s11307-011-0474-6DOI Listing
February 2012

In vivo imaging of immune cell trafficking in cancer.

Eur J Nucl Med Mol Imaging 2011 May 18;38(5):949-68. Epub 2010 Dec 18.

Department of Biomedical Sciences and Technologies, University of Milan, Milan, Italy.

Tumour establishment, progression and regression can be studied in vivo using an array of imaging techniques ranging from MRI to nuclear-based and optical techniques that highlight the intrinsic behaviour of different cell populations in the physiological context. Clinical in vivo imaging techniques and preclinical specific approaches have been used to study, both at the macroscopic and microscopic level, tumour cells, their proliferation, metastasisation, death and interaction with the environment and with the immune system. Fluorescent, radioactive or paramagnetic markers were used in direct protocols to label the specific cell population and reporter genes were used for genetic, indirect labelling protocols to track the fate of a given cell subpopulation in vivo. Different protocols have been proposed to in vivo study the interaction between immune cells and tumours by different imaging techniques (intravital and whole-body imaging). In particular in this review we report several examples dealing with dendritic cells, T lymphocytes and macrophages specifically labelled for different imaging procedures both for the study of their physiological function and in the context of anti-neoplastic immunotherapies in the attempt to exploit imaging-derived information to improve and optimise anti-neoplastic immune-based treatments.
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http://dx.doi.org/10.1007/s00259-010-1687-7DOI Listing
May 2011