Page 1 of 4
Mitochondria Transfer from Mesenchymal Stem Cells Confers Chemoresistance to Glioblastoma Stem Cells through Metabolic Rewiring
Abstract:
Glioblastomas (GBM) are heterogeneous tumors with high metabolic plasticity. Their poor prognosis is linked to the presence of glioblastoma stem cells (GSC), which support resistance to therapy, notably to temozolomide (TMZ). Mesenchymal stem cells (MSC) recruitment to GBM contributes to GSC chemoresistance, by mechanisms still poorly understood. Here, we provide evidence that MSCs transfer mitochondria to GSCs through tunneling nanotubes, which enhances GSCs resistance to TMZ. More precisely, our metabolomics analyses reveal that MSC mitochondria induce GSCs metabolic reprograming, with a nutrient shift from glucose to glutamine, a rewiring of the tricarboxylic acid cycle from glutaminolysis to reductive carboxylation and increase in orotate turnover as well as in pyrimidine and purine synthesis. Metabolomics analysis of GBM patient tissues at relapse after TMZ treatment documents increased concentrations of AMP, CMP, GMP, and UMP nucleotides and thus corroborate our in vitro analyses. Finally, we provide a mechanism whereby mitochondrial transfer from MSCs to GSCs contributes to GBM resistance to TMZ therapy, by demonstrating that inhibition of orotate production by Brequinar (BRQ) restores TMZ sensitivity in GSCs with acquired mitochondria. Altogether, these results identify a mechanism for GBM resistance to TMZ and reveal a metabolic dependency of chemoresistant GBM following the acquisition of exogenous mitochondria, which opens therapeutic perspectives based on synthetic lethality between TMZ and BRQ.
Mitochondria acquired from MSCs enhance the chemoresistance of GBMs. The discovery that they also generate metabolic vulnerability in GSCs paves the way for novel therapeutic approaches.
Deciphering the Action of Neuraminidase in Glioblastoma Models
Nathalie Baeza-Kallee,Raphaël Bergès,Victoria Hein ,Stéphanie Cabaret ,Jeremy Garcia ,Abigaëlle Gros,Emeline Tabouret,Aurélie Tchoghandjian ,Carole Colin andDominique Figarella-Branger
Int. J. Mol. Sci. 2023, 24(14), 11645; https://doi.org/10.3390/ijms241411645
Abstract
Reuniting philosophy and science to advance cancer research
Biological Reviews (2023)
Thomas Pradeu, Bertrand Daignan-Fornier, Andrew Ewald, Pierre-Luc Germain, Samir Okasha, Anya Plutynski, Sébastien Benzekry, Marta Bertolaso, Mina Bissell, Joel S. Brown, Benjamin Chin-Yee, Ian Chin-Yee, Hans Clevers, Laurent Cognet, Marie Darrason, Emmanuel Farge, Jean Feunteun, Jérôme Galon, Elodie Giroux, Sara Green, Fridolin Gross, Fanny Jaulin, Rob Knight, Ezio Laconi, Nicolas Larmonier, Carlo Maley, Alberto Mantovani, Violaine Moreau, Pierre Nassoy, Elena Rondeau, David Santamaria, Catherine M. Sawai, Andrei Seluanov, Gregory D. Sepich-Poore, Vanja Sisirak, Eric Solary, Sarah Yvonnet, Lucie Laplane
ABSTRACT
Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer. We argue that one important way forward in service of a more successful dialogue is through greater integration of applied sciences (experimental and clinical) with conceptual and theoretical approaches, informed by philosophical methods. By way of illustration, we explore six central themes: (i) the role of mutations in cancer; (ii) the clonal evolution of cancer cells; (iii) the relationship between cancer and multicellularity; (iv) the tumour microenvironment; (v) the immune system; and (vi) stem cells. In each case, we examine open questions in the scientific literature through a philosophical methodology and show the benefit of such a synergy for the scientific and medical understanding of cancer.
Disruption of lineage integrity as a precursor to breast tumor initiation
DOI: https://doi.org/10.1016/j.tcb.2023.03.010
Abstract
A new natural killer cell-specific gene signature predicting recurrence in colorectal cancer patients
Carolyn Shembrey , Momeneh Foroutan , Frédéric Hollande
Front Immunol. 2023 Jan 6;13:1011247. doi: 10.3389/fimmu.2022.1011247
Abstract
The protective role of Natural Killer (NK) cell tumour immunosurveillance has long been recognised in colorectal cancer (CRC). However, as most patients show limited intra-tumoral NK cell infiltration, improving our ability to identify those with high NK cell activity might aid in dissecting the molecular features which underlie NK cell sensitivity. Here, a novel CRC-specific NK cell gene signature that infers NK cell load in primary tissue samples was derived and validated in multiple patient CRC cohorts. In contrast with other NK cell gene signatures that have several overlapping genes across different immune cell types, our NK cell signature has been extensively refined to be specific for CRC-infiltrating NK cells. The specificity of the signature is substantiated in tumour-infiltrating NK cells from primary CRC tumours at the single cell level, and the signature includes genes representative of NK cells of different maturation states, activation status and anatomical origin. Our signature also accurately discriminates murine NK cells, demonstrating the applicability of this geneset when mining datasets generated from preclinical studies. Differential gene expression analysis revealed tumour-intrinsic features associated with NK cell inclusion versus exclusion in CRC patients, with those tumours with predicted high NK activity showing strong evidence of enhanced chemotactic and cytotoxic transcriptional programs. Furthermore, survival modelling indicated that NK signature expression is associated with improved survival outcomes in CRC patients. Thus, scoring CRC samples with this refined NK cell signature might aid in identifying patients with high NK cell activity who could be prime candidates for NK cell directed immunotherapies.
ABSP: an automated R tool to efficiently analyze region-specific CpG methylation from bisulfite sequencing PCR
Denoulet M, Brulé M, Anquez F, Vincent A, Schnipper J, Adriaenssens E, Toillon RA, Le Bourhis X, Lagadec C.
Bioinformatics. 2023 Jan 1;39(1):btad008. doi: 10.1093/bioinformatics/btad008. PMID: 36629453; PMCID: PMC9846423.
Abstract
Nowadays, epigenetic gene regulations are studied in each part of the biology, from embryonic development to diseases such as cancers and neurodegenerative disorders. Currently, to quantify and compare CpG methylation levels of a specific region of interest, the most accessible technique is the bisulfite sequencing PCR (BSP). However, no existing user-friendly tool is able to analyze data from all approaches of BSP. Therefore, the most convenient way to process results from the direct sequencing of PCR products (direct-BSP) is to manually analyze the chromatogram traces, which is a repetitive and prone to error task.
Here, we implement a new R-based tool, called ABSP for analysis of bisulfite sequencing PCR, providing a complete analytic process of both direct-BSP and cloning-BSP data. It uses the raw sequencing trace files (.ab1) as input to compute and compare CpG methylation percentages. It is fully automated and includes a user-friendly interface as a built-in R shiny app, quality control steps and generates publication-ready graphics.
The ABSP tool and associated data are available on GitHub at https://github.com/ABSP-methylation-tool/ABSP.
Basal-like mammary carcinomas stimulate cancer stem cell properties through AXL-signaling to induce chemotherapy resistance
Garyfallia Pantelaiou-Prokaki, Oliver Reinhardt, Nadine S. Georges, David J. Agorku, Olaf Hardt, Evangelos Prokakis, Iga K. Mieczkowska, Wolfgang Deppert, Florian Wegwitz, Frauke Alves
MOLECULAR CANCER BIOLOGY
Abstract
Basal-like breast cancer (BLBC) is the most aggressive and heterogeneous breast cancer (BC) subtype. Conventional chemotherapies represent next to surgery the most frequently employed treatment options. Unfortunately, resistant tumor phenotypes often develop, resulting in therapeutic failure. To identify the early events occurring upon the first drug application and initiating chemotherapy resistance in BLBC, we leveraged the WAP-T syngeneic mammary carcinoma mouse model and we developed a strategy combining magnetic-activated cell sorting (MACS)-based tumor cell enrichment with high-throughput transcriptome analyses. We discovered that chemotherapy induced a massive gene expression reprogramming toward stemness acquisition to tolerate and survive the cytotoxic treatment in vitro and in vivo. Retransplantation experiments revealed that one single cycle of cytotoxic drug combination therapy (Cyclophosphamide, Adriamycin and 5-Fluorouracil) suffices to induce resistant tumor cell phenotypes in vivo. We identified Axl and its ligand Pros1 as highly induced genes driving cancer stem cell (CSC) properties upon chemotherapy in vivo and in vitro. Furthermore, from our analysis of BLBC patient datasets, we found that AXL expression is also strongly correlated with CSC-gene signatures, a poor response to conventional therapies and worse survival outcomes in those patients. Finally, we demonstrate that AXL inhibition sensitized BLBC-cells to cytotoxic treatment in vitro. Together, our data support AXL as a promising therapeutic target to optimize the efficiency of conventional cytotoxic therapies in BLBC.
CD44v3 is a marker of invasive cancer stem cells driving metastasis in gastric carcinoma
Julie Giraud, Lornella Seeneevassen, Benoit Rousseau, Damien Bouriez, Elodie Sifré, Alban Giese, Tra Ly Nguyen, Camille Tiffon, Yannick Lippi, Lamia Azzi-Martin, Julie Pannequin, Armelle Ménard, Emilie Bessède, Cathy Staedel, Francis Mégraud, Geneviève Belleannée, Philippe Lehours, Caroline Gronnier, Pierre Dubus & Christine Varon
Gastric Cancer (2022)
Abstract
Background
Cancer stem cells (CSCs) are at the origin of tumour initiation and progression in gastric adenocarcinoma (GC). However, markers of metastasis-initiating cells remain unidentified in GC. In this study, we characterized CD44 variants expressed in GC and evaluated the tumorigenic and metastatic properties of CD44v3+?cells and their clinical significance in GC patients.
Methods
Using GC cell lines and patient-derived xenografts, we evaluated CD44+?and CD44v3+?GC cells molecular signature and their tumorigenic, chemoresistance, invasive and metastatic properties, and expression in patients-derived tissues.
Results
CD44v3+?cells, which represented a subpopulation of CD44+?cells, were detected in advanced preneoplastic lesions and presented CSCs chemoresistance and tumorigenic properties in vitro and in vivo. Molecular and functional analyses revealed two subpopulations of gastric CSCs: CD44v3+?CSCs with an epithelial-mesenchymal transition (EMT)-like signature, and CD44+/v3– CSCs with an epithelial-like signature; both were tumorigenic but CD44v3+ cells showed higher invasive and metastatic properties in vivo. CD44v3+?cells detected in the primary tumours of GC patients were associated with a worse prognosis.
Conclusion
CD44v3 is a marker of a subpopulation of CSCs with metastatic properties in GC. The identification of metastasis-initiating cells in GC represents a major advance for further development of anti-metastatic therapeutic strategies.
Challenges in glioblastoma research: focus on the tumor microenvironment
Trends in Cancer, 16 Nov 2022, 9(1):9-27
DOI: 10.1016/j.trecan.2022.09.005 PMID: 36400694
Glioblastoma (GBM) is the most deadly type of malignant brain tumor, despite extensive molecular analyses of GBM cells. In recent years, the tumor microenvironment (TME) has been recognized as an important player and therapeutic target in GBM. However, there is a need for a full and integrated understanding of the different cellular and molecular components involved in the GBM TME and their interactions for the development of more efficient therapies. In this review, we provide a comprehensive report of the GBM TME, which assembles the contributions of physicians and translational researchers working on brain tumor pathology and therapy in France. We propose a holistic view of the subject by delineating the specific features of the GBM TME at the cellular, molecular, and therapeutic levels.
Emerging Roles of Hedgehog Signaling in Cancer Immunity
Int. J. Mol. Sci. 2023, 24(2), 1321; https://doi.org/10.3390/ijms24021321
Abstract
Production of CRISPRi-engineered primary human mammary epithelial cells with baboon envelope pseudotyped lentiviral vectors
Sonia Pastor 1, Julien Wicinski 2, Emmanuelle Charafe-Jauffret 2, Els Verhoeyen 3, Geoffrey Guittard 4, Christophe Ginestier 5
STAR PROTOCOL 2023 Jan 19;4(1):102055
doi: 10.1016/j.xpro.2023.102055
Primary human mammary epithelial cells (pHMECs) are known to be remarkably difficult to engineer genetically. Here, we present a protocol for efficient transduction of pHMECs using a baboon retroviral envelope glycoprotein for pseudotyping of lentiviral vectors (BaEV-LVs). We describe the preparation of the BaEV-LVs, the isolation of pHMECs from breast samples, and the subsequent transduction of pHMECs. We also detail the use of CRISPRi technology to efficiently silence gene expression in pHMECs, which can then be used for functional assays. For complete details on the use and execution of this protocol, please refer to Richart et al. (2022).1.
Ras/MAPK signalling intensity defines subclonal fitness in a mouse model of primary and metastatic hepatocellular carcinoma
Lozano A., Souche FR., Chavey C., Dardalhon V., Ramirez C., Vegna S., Desandre? G., Riviere A., , Zine El Aabidine A., Fort P., Akkari L., Hibner U. , Gregoire D.
eLife; 12:e76294
Abstract:
Quantitative differences in signal transduction are to date an understudied feature of tumour heterogeneity. The MAPK Erk pathway, which is activated in a large proportion of human tumours, is a prototypic example of distinct cell fates being driven by signal intensity. We have used primary hepatocyte precursors transformed with different dosages of an oncogenic form of Ras to model subclonal variations in MAPK signalling. Orthotopic allografts of Ras-transformed cells in immunocompromised mice gave rise to fast-growing aggressive tumours, both at the primary location and in the peritoneal cavity. Fluorescent labelling of cells expressing different oncogene levels, and consequently varying levels of MAPK Erk activation, highlighted the selection processes operating at the two sites of tumour growth. Indeed, significantly higher Ras expression was observed in primary as compared to secondary, metastatic sites, despite the apparent evolutionary trade-off of increased apoptotic death in the liver that correlated with high Ras dosage. Analysis of the immune tumour microenvironment at the two locations suggests that fast peritoneal tumour growth in the immunocompromised setting is abrogated in immunocompetent animals due to efficient antigen presentation by peritoneal dendritic cells. Furthermore, our data indicate that, in contrast to the metastatic-like outgrowth, strong MAPK signalling is required in the primary liver tumours to resist elimination by NK (natural killer) cells. Overall, this study describes a quantitative aspect of tumour heterogeneity and points to a potential vulnerability of a subtype of hepatocellular carcinoma as a function of MAPK Erk signalling intensity.
Stochasticity and Drug Effects in Dynamical Model for Cancer Stem Cells
Cancers 2023, 15(3), 677; https://doi.org/10.3390/cancers15030677
Abstract
ROBO3s: a novel ROBO3 short isoform promoting breast cancer aggressiveness
Marcel Werner, Anna Dyas, Iwan Parfentev, Geske E Schmidt, Iga K Mieczkowska , Lukas C Müller-Kirschbaum , Claudia Müller , Stefan Kalkhof , Oliver Reinhardt , Henning Urlaub, Frauke Alves, Julia Gallwas, Evangelos Prokakis, Florian Wegwitz
Basal-like breast cancer (BLBC) is a highly aggressive breast cancer subtype frequently associated with poor prognosis. Due to the scarcity of targeted treatment options, conventional cytotoxic chemotherapies frequently remain the standard of care. Unfortunately, their efficacy is limited as BLBC malignancies rapidly develop resistant phenotypes. Using transcriptomic and proteomic approaches in human and murine BLBC cells, we aimed to elucidate the molecular mechanisms underlying the acquisition of aggressive and chemotherapy-resistant phenotypes in these mammary tumors. Specifically, we identified and characterized a novel short isoform of Roundabout Guidance Receptor 3 (ROBO3s), upregulated in BLBC in response to chemotherapy and encoding for a protein variant lacking the transmembrane domain. We established an important role for the ROBO3s isoform, mediating cancer stem cell properties by stimulating the Hippo-YAP signaling pathway, and thus driving resistance of BLBC cells to cytotoxic drugs. By uncovering the conservation of ROBO3s expression across multiple cancer types, as well as its association with reduced BLBC-patient survival, we emphasize its potential as a prognostic marker and identify a novel attractive target for anti-cancer drug development.
A2B5 Expression in Central Nervous System and Gliomas
Dominique Figarella-Branger , Carole Colin , Nathalie Baeza-Kallee , Aurélie Tchoghandjian
A2B5 IgM recognizes c-series gangliosides with three sialic acids. The aim of this review was to focus on A2B5 expression in the central nervous system and gliomas. In brain development, A2B5+ cells are recorded in areas containing multipotent neural stem cells (NSC). In adults, A2B5+ cells persist in neurogenic areas and in white matter where it identifies oligodendrocyte precursor cells (OPCs) but also cells with NSC properties. Although the expression of A2B5 has been widely studied in culture, where it characterizes bipotential glial progenitor cells, its expression in vivo is less characterized mainly because of technical issues. A new interest was given to the NSCs and OPCs since the discovery of cancer stem cells (CSC) in gliomas. Among other cell surface molecules, A2B5 has been identified as an accurate marker to identify glioma CSCs. We and others have shown that all types of gliomas express A2B5, and that only A2B5+ cells, and not A2B5- cells, can generate a tumor after orthotopic implantation in immunocompromised animals. Moreover, A2B5 epitope expression is positively correlated with stemness and tumor growth. This review highlights that A2B5 is an attractive target to tackle glioma CSCs, and a better characterization of its expression in the developing and adult CNS will benefit to a better understanding of gliomagenesis.
Comparative roadmaps of reprogramming and oncogenic transformation identify Bcl11b and Atoh8 as broad regulators of cellular plasticity
A. Huyghe, G. Furlan, J. Schroeder, E. Cascales, A. Trajkova, M. Ruel, F. Stüder, M. Larcombe, Y. Bo Yang Sun, F. Mugnier, L. De Matteo, A. Baygin, J. Wang, Y. Yu, N. Rama, B. Gibert, J. Kielbassa, L. Tonon, P. Wajda, N. Gadot, M. Brevet, M. Siouda, P. Mulligan, R. Dante, P. Liu, H. Gronemeyer, M. Mendoza-Parra, J. M. Polo & F. Lavial
Nature Cell Biology volume 24, pages1350–1363 (2022)
Abstract
Coordinated changes of cellular plasticity and identity are critical for pluripotent reprogramming and oncogenic transformation. However, the sequences of events that orchestrate these intermingled modifications have never been comparatively dissected. Here, we deconvolute the cellular trajectories of reprogramming (via Oct4/Sox2/Klf4/c-Myc) and transformation (via Ras/c-Myc) at the single-cell resolution and reveal how the two processes intersect before they bifurcate. This approach led us to identify the transcription factor Bcl11b as a broad-range regulator of cell fate changes, as well as a pertinent marker to capture early cellular intermediates that emerge simultaneously during reprogramming and transformation. Multiomics characterization of these intermediates unveiled a c-Myc/Atoh8/Sfrp1 regulatory axis that constrains reprogramming, transformation and transdifferentiation. Mechanistically, we found that Atoh8 restrains cellular plasticity, independent of cellular identity, by binding a specific enhancer network. This study provides insights into the partitioned control of cellular plasticity and identity for both regenerative and cancer biology.
Multivariate Analysis of RNA Chemistry Marks Uncovers Epitranscriptomics-Based Biomarker Signature for Adult Diffuse Glioma Diagnostics
S. Relier; A. Amalric; A. Attina; I.B. Koumare; V. Rigau; F. Burel Vandenbos; D. Fontaine; M. Baroncini; J.P. Hugnot; H. Duffau; L. Bauchet; C. Hirtz*; E. Rivals* & A. David*
Anal. Chem. 2022
One of the main challenges in cancer management relates to the discovery of reliable biomarkers, which could guide decision-making and predict treatment outcome. In particular, the rise and democratization of high-throughput molecular profiling technologies bolstered the discovery of “biomarker signatures” that could maximize the prediction performance. Such an approach was largely employed from diverse OMICs data (i.e., genomics, transcriptomics, proteomics, metabolomics) but not from epitranscriptomics, which encompasses more than 100 biochemical modifications driving the post-transcriptional fate of RNA: stability, splicing, storage, and translation. We and others have studied chemical marks in isolation and associated them with cancer evolution, adaptation, as well as the response to conventional therapy. In this study, we have designed a unique pipeline combining multiplex analysis of the epitranscriptomic landscape by high-performance liquid chromatography coupled to tandem mass spectrometry with statistical multivariate analysis and machine learning approaches in order to identify biomarker signatures that could guide precision medicine and improve disease diagnosis. We applied this approach to analyze a cohort of adult diffuse glioma patients and demonstrate the existence of an “epitranscriptomics-based signature” that permits glioma grades to be discriminated and predicted with unmet accuracy. This study demonstrates that epitranscriptomics (co)evolves along cancer progression and opens new prospects in the field of omics molecular profiling and personalized medicine.
Genome-wide RNA interference screen in cancer stem cell
Guillaume Pinna 1, Marie Vandamme 1, Celia Rouault 2, Emmanuelle Charafe-Jauffret 2, Christophe Ginestier 3
- 1Plateforme ARN interférence (PARi), Université Paris Cité & Université Paris-Saclay, Inserm, iRCM/IBFJ CEA, Stabilité Génétique Cellules Souches et Radiations, Fontenay-aux-Roses, France.
- 2CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille Université, Epithelial Stem Cells and Cancer Lab, Equipe labellisée LIGUE contre le cancer, Marseille, France.
- 3CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille Université, Epithelial Stem Cells and Cancer Lab, Equipe labellisée LIGUE contre le cancer, Marseille, France. Electronic address: christophe.ginestier@inserm.fr.
Tumor heterogeneity represents a major hurdle for therapy. This cellular heterogeneity is mainly sustained by different subpopulations of tumorigenic cells, the so-called cancer stem cells (CSCs). CSCs burden is associated with disease progression and patient poor prognosis. In this context, deciphering molecular mechanisms regulating stemness is a key step in the development of new therapeutic strategy. Here, we provide a detailed protocol for high-throughput screening (HTS) strategy to detect modulators of CSC proportion. It is based on a miniaturized ALDEFLUOR-probed CSC assay quantitated by high-content imaging, that allows monitoring the changes in CSC proportions in response to gene silencing. Gene loss-of-function is achieved by transfecting a genome-wide RNA interference library. These genome-wide HTS strategies could lead to the identification of new therapeutic approaches in the treatment of various cancers.
XIST loss impairs mammary stem cell differentiation and increases tumorigenicity through Mediator hyperactivation
Laia Richart 1, Mary-Loup Picod-Chedotel 2, Michel Wassef 1, Manon Macario 2, Setareh Aflaki 1, Marion A Salvador 2, Tiphaine Héry 1, Aurélien Dauphin 1, Julien Wicinski 2, Véronique Chevrier 2, Sonia Pastor 3, Geoffrey Guittard 3, Samuel Le Cam 1, Hanya Kamhawi 2, Rémy Castellano 4, Géraldine Guasch 2, Emmanuelle Charafe-Jauffret 5, Edith Heard 6, Raphaël Margueron 7, Christophe Ginestier 8
Cell, 2022 May 13;S0092-8674(22)00532-3
Summary
Paracrine signalling between intestinal epithelial and tumour cells induces a regenerative programme
Guillaume Jacquemin, Annabelle Wurmser, Mathilde Huyghe, Wenjie Sun, Zeinab Homayed, Candice Merle, Meghan Perkins, Fairouz Qasrawi, Sophie Richon, Florent Dingli, Guillaume Arras, Damarys Loew, Danijela Vignjevic, Julie Pannequin, Silvia Fre
Abstract
Tumours are complex ecosystems composed of different types of cells that communicate and influence each other. While the critical role of stromal cells in affecting tumour growth is well established, the impact of mutant cancer cells on healthy surrounding tissues remains poorly defined. Here, using mouse intestinal organoids, we uncover a paracrine mechanism by which intestinal cancer cells reactivate foetal and regenerative YAP-associated transcriptional programmes in neighbouring wildtype epithelial cells, rendering them adapted to thrive in the tumour context. We identify the glycoprotein thrombospondin-1 (THBS1) as the essential factor that mediates non-cell-autonomous morphological and transcriptional responses. Importantly, Thbs1 is associated with bad prognosis in several human cancers. This study reveals the THBS1-YAP axis as the mechanistic link mediating paracrine interactions between epithelial cells in intestinal tumours.
Page 1 of 4