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Alexandre Calon,
Elisa Espinet,
Sergio Palomo-Ponce,
Daniele V F Tauriello, Mar Iglesias,
María Virtudes Céspedes,
Marta Sevillano,
Cristina Nadal,
Peter Jung,
Xiang H-F Zhang,
Daniel Byrom,
Antoni Riera,
David Rossell,
Ramón Mangues,
Joan Massagué,
Elena Sancho,
Eduard Batlle
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Alexandre Calon,
Elisa Espinet,
Sergio Palomo-Ponce,
Daniele V F Tauriello, Mar Iglesias,
María Virtudes Céspedes,
Marta Sevillano,
Cristina Nadal,
Peter Jung,
Xiang H-F Zhang,
Daniel Byrom,
Antoni Riera,
David Rossell,
Ramón Mangues,
Joan Massagué,
Elena Sancho,
Eduard Batlle
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Gastroenterología y Hepatología 01/2013; · 0.73 Impact Factor
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Alexandre Calon,
Elisa Espinet,
Sergio Palomo-Ponce,
Daniele V F Tauriello, Mar Iglesias,
María Virtudes Céspedes,
Marta Sevillano,
Cristina Nadal,
Peter Jung,
Xiang H-F Zhang,
Daniel Byrom,
Antoni Riera,
David Rossell,
Ramón Mangues,
Joan Massagué,
Elena Sancho,
Eduard Batlle
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ABSTRACT: A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-β pathway, yet, paradoxically, they are characterized by elevated TGF-β production. Here, we unveil a prometastatic program induced by TGF-β in the microenvironment that associates with a high risk of CRC relapse upon treatment. The activity of TGF-β on stromal cells increases the efficiency of organ colonization by CRC cells, whereas mice treated with a pharmacological inhibitor of TGFBR1 are resilient to metastasis formation. Secretion of IL11 by TGF-β-stimulated cancer-associated fibroblasts (CAFs) triggers GP130/STAT3 signaling in tumor cells. This crosstalk confers a survival advantage to metastatic cells. The dependency on the TGF-β stromal program for metastasis initiation could be exploited to improve the diagnosis and treatment of CRC.
Cancer cell 11/2012; 22(5):571-84. · 25.29 Impact Factor
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ABSTRACT: Studies in animal models and humans suggest anti-inflammatory roles on the N-acylethanolamide (NAE)-peroxisome proliferators activated receptor alpha (PPARα) system in inflammatory bowel diseases. However, the presence and function of NAE-PPARα signaling system in the ulcerative colitis (UC) of humans remain unknown as well as its response to active anti-inflammatory therapies such as 5-aminosalicylic acid (5-ASA) and glucocorticoids. Expression of PPARα receptor and PPARα ligands-biosynthetic (NAPE-PLD) and -degrading (FAAH and NAAA) enzymes were analyzed in untreated active and 5-ASA/glucocorticoids/immunomodulators-treated quiescent UC patients compared to healthy human colonic tissue by RT-PCR and immunohistochemical analyses. PPARα, NAAA, NAPE-PLD and FAAH showed differential distributions in the colonic epithelium, lamina propria, smooth muscle and enteric plexus. Gene expression analysis indicated a decrease of PPARα, PPARγ and NAAA, and an increase of FAAH and iNOS in the active colitis mucosa. Immunohistochemical expression in active colitis epithelium confirmed a PPARα decrease, but showed a sharp NAAA increase and a NAPE-PLD decrease, which were partially restored to control levels after treatment. We also characterized the immune cells of the UC mucosa infiltrate. We detected a decreased number of NAAA-positive and an increased number of FAAH-positive immune cells in active UC, which were partially restored to control levels after treatment. NAE-PPARα signaling system is impaired during active UC and 5-ASA/glucocorticoids treatment restored its normal expression. Since 5-ASA actions may work through PPARα and glucocorticoids through NAE-producing/degrading enzymes, the use of PPARα agonists or FAAH/NAAA blockers that increases endogenous PPARα ligands may yield similar therapeutics advantages.
PLoS ONE 01/2012; 7(5):e37729. · 4.09 Impact Factor
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Elena Ortiz-Zapater,
David Pineda,
Neus Martínez-Bosch,
Gonzalo Fernández-Miranda, Mar Iglesias,
Francesc Alameda,
Mireia Moreno,
Carolina Eliscovich,
Eduardo Eyras,
Francisco X Real,
Raúl Méndez,
Pilar Navarro
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ABSTRACT: Malignant transformation, invasion and angiogenesis rely on the coordinated reprogramming of gene expression in the cells from which the tumor originated. Although deregulated gene expression has been extensively studied at genomic and epigenetic scales, the contribution of the regulation of mRNA-specific translation to this reprogramming is not well understood. Here we show that cytoplasmic polyadenylation element binding protein 4 (CPEB4), an RNA binding protein that mediates meiotic mRNA cytoplasmic polyadenylation and translation, is overexpressed in pancreatic ductal adenocarcinomas and glioblastomas, where it supports tumor growth, vascularization and invasion. We also show that, in pancreatic tumors, the pro-oncogenic functions of CPEB4 originate in the translational activation of mRNAs that are silenced in normal tissue, including the mRNA of tissue plasminogen activator, a key contributor to pancreatic ductal adenocarcinoma malignancy. Taken together, our results document a key role for post-transcriptional gene regulation in tumor development and describe a detailed mechanism for gene expression reprogramming underlying malignant tumor progression.
Nature medicine 12/2011; 18(1):83-90. · 27.14 Impact Factor
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Daniel Castillo,
Sonia Puig, Mar Iglesias,
Agustín Seoane,
Carme de Bolós,
Vicente Munitiz,
Pascual Parrilla,
Laura Comerma,
Richard Poulsom,
Kausilia K Krishnadath,
Luís Grande,
Manuel Pera
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ABSTRACT: A human model of gastroesophageal reflux disease was used to examine the contribution of a non-specialized columnar type of metaplasia (NSCM) and key molecular events (BMP4 and CDX2) in the development of Barrett's esophagus.
Biopsies of the remnant esophagus from 18 patients undergoing esophagectomy with gastric preservation were taken at 6-36-month intervals postoperatively and examined for activation of the BMP pathway (BMP4/P-Smad 1/5/8) and CDX2 and CDX1 expression by imunohistochemistry, quantitative real-time PCR, Western blot, and in situ hybridization.
A short segment (mean 15.6 mm) of NSCM was detected in 10 (56%) patients, with an increasing prevalence from 17% at 6 months to 62% at 36 months. Nuclear expression of P-Smad 1/5/8 in the squamous epithelium close to the anastomosis with strong expression in all epithelial cells of NSCM areas was found. Forty-eight (63%) biopsies with NSCM showed scattered nuclear expression of CDX2. Two cases showed isolated glands at 18, 24, and 36 months that fully expressed CDX2 and co-expressed CDX1. BMP4 mRNA and CDX2 mRNA levels were significantly greater in NSCM than in squamous epithelium.
BMP4 activation in NSCM and early expression of CDX2 are involved in the columnar epithelial differentiation of Barrett's esophagus.
Journal of Gastrointestinal Surgery 11/2011; 16(2):227-37; discussion 237. · 2.83 Impact Factor
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Peter Jung,
Toshiro Sato,
Anna Merlos-Suárez,
Francisco M Barriga, Mar Iglesias,
David Rossell,
Herbert Auer,
Mercedes Gallardo,
Maria A Blasco,
Elena Sancho,
Hans Clevers,
Eduard Batlle
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ABSTRACT: Here we describe the isolation of stem cells of the human colonic epithelium. Differential cell surface abundance of ephrin type-B receptor 2 (EPHB2) allows the purification of different cell types from human colon mucosa biopsies. The highest EPHB2 surface levels correspond to epithelial colonic cells with the longest telomeres and elevated expression of intestinal stem cell (ISC) marker genes. Moreover, using culturing conditions that recreate the ISC niche, a substantial proportion of EPHB2-high cells can be expanded in vitro as an undifferentiated and multipotent population.
Nature medicine 09/2011; 17(10):1225-7. · 27.14 Impact Factor
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Xavier Bessa,
Cristina Alenda,
Artemio Paya,
Cristina Álvarez, Mar Iglesias,
Agustín Seoane,
Josep Maria Dedeu,
Anna Abulí,
Lucas Ilzarbe,
Gemma Navarro,
Maria Pellise,
Francesc Balaguer,
Sergi Castellvi-Bel,
Xavier Llor,
Antoni Castells,
Rodrigo Jover,
Montserrat Andreu
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ABSTRACT: Bethesda guidelines are used to recognize patients at risk for Lynch syndrome. However, obtaining personal and familial tumor data can sometimes be difficult. The Microsatellite Path Score (MsPath), a pathological score, based on age, tumor location, and pathologic features, has been developed to effectively predict colorectal cancer with DNA mismatch repair (MMR) deficiencies. However, the MsPath model's performance in an unselected, population-based colorectal cancer (CRC) population is unknown.
We analyzed all patients with CRC regardless of age, personal or family history, and tumor characteristics from the EPICOLON study, an independent, prospective, multicenter, population-based cohort (N = 1,222). All patients underwent tumor microsatellite instability (MSI) analysis and immunostaining for MLH1/MSH2, and those with MMR underwent tumor BRAF mutation analysis and MLH1/MSH2 germline testing. All the pathologic features were centralized and evaluated blinded to the MMR status.
MsPath score for prediction of having MSI high, with the recommended MsPath cutoff score ≥1.0, had a sensitivity, specificity, and positive predictive value (PPV) of 92.8% (95% CI, 86.9 to 98.3), 64.1% (95% CI, 61.1 to 66.8), and 15.8% (95% CI, 12.2 to 18.6), respectively. MsPath score had a sensitivity, specificity, and PPV of 81.8% (95% CI, 59.0 to 99.8), 60.6% (95% CI, 57.8 to 63.4), and 1.9% (95% CI, 0.7 to 3.1), respectively, for the identification of MLH1/MSH2 gene carriers. Application of the MsPath score, resulted in two (18%) of 11 mutation carriers being missed, both pathogenic germline MSH2 mutations.
In the general nonselected population, the MsPath score accurately predicted the probability of bearing a MSI high CRC, but it was insufficiently accurate to use for the selection of patients warranting MLH1/MSH2 mutation testing in the setting of Lynch syndrome.
Journal of Clinical Oncology 07/2011; 29(25):3374-80. · 18.37 Impact Factor
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Anna Merlos-Suárez,
Francisco M Barriga,
Peter Jung, Mar Iglesias,
María Virtudes Céspedes,
David Rossell,
Marta Sevillano,
Xavier Hernando-Momblona,
Victoria da Silva-Diz,
Purificación Muñoz,
Hans Clevers,
Elena Sancho,
Ramón Mangues,
Eduard Batlle
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ABSTRACT: A frequent complication in colorectal cancer (CRC) is regeneration of the tumor after therapy. Here, we report that a gene signature specific for adult intestinal stem cells (ISCs) predicts disease relapse in CRC patients. ISCs are marked by high expression of the EphB2 receptor, which becomes gradually silenced as cells differentiate. Using EphB2 and the ISC marker Lgr5, we have FACS-purified and profiled mouse ISCs, crypt proliferative progenitors, and late transient amplifying cells to define a gene program specific for normal ISCs. Furthermore, we discovered that ISC-specific genes identify a stem-like cell population positioned at the bottom of tumor structures reminiscent of crypts. EphB2 sorted ISC-like tumor cells display robust tumor-initiating capacity in immunodeficient mice as well as long-term self-renewal potential. Taken together, our data suggest that the ISC program defines a cancer stem cell niche within colorectal tumors and plays a central role in CRC relapse.
Cell stem cell 03/2011; 8(5):511-24. · 23.56 Impact Factor
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ABSTRACT: Most sporadic gastrointestinal stromal tumors occur as solitary lesions, whereas a multicentric appearance involving the stomach, the small intestine, or both sites is suspicious for lesions developed in the setting of hereditary or idiopathic tumor syndromes or metastatic disease. The rare occurrence of multiple sporadic gastrointestinal stromal tumors has been recently reported in the literature. Here, we report a case of multiple sporadic gastrointestinal stromal tumors affecting the small intestine in a 61-year-old man, unique with regard to the number of lesions (>30) and the molecular profile. Four different mutations of KIT involving exons 11, 13, and 17 were present among 4 of 10 excised tumors. In addition, BRAF p.V600E mutation was detected in 5 tumors and was mutually exclusive with KIT mutations. To our knowledge, this is the first time a case of a synchronic multisporadic gastrointestinal stromal tumor outstanding for the high number of lesions, which are of independent origin, is reported.
Human pathology 02/2011; 42(8):1194-9. · 3.03 Impact Factor
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Peter Jung,
Toshiro Sato,
Anna Merlos-Suárez,
Francisco M Barriga, Mar Iglesias,
David Rossell,
María M Gallardo,
Maria A Blasco,
Elena Sancho,
Hans Clevers,
Eduard Batlle
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ABSTRACT: B r i e f c o m m u n i c at i o n s nature medicine advance online publication Throughout the human lifespan, colon stem cells (CoSCs) renew the epithelium that lines the large intestine 1 . It is believed that alterations in the biology of CoSCs account for the pathophysiology of various large-bowel disorders, including colorectal cancer 2 . Yet the identifica-tion of CoSCs remains elusive. The EPHB2 gene encodes a receptor tyrosine kinase whose activity in mouse intestine is required to posi-tion different cell types along the crypt axis 3 . High amounts of EPHB2 characterize mouse small intestine ISCs as well as colorectal cancer stem cells 4 . In human colon epithelium, EPHB2 cell abundance was maximal at the bottom of crypts and decreased along a gradient as epithelial cells migrated upward (Fig. 1a and Supplementary Fig. 1). Cells within the crypt proliferation compartment (MKI67 + domain) had heterogeneous amounts of EPHB2, whereas differentiated cells of the surface epithe-lium (keratin 20 positive, KRT20 +) stained negative for EPHB2 (Fig. 1a and Supplementary Fig. 1). Using an antibody against the extracellular domain of EPHB2, we purified intestinal epithelial cells from normal fresh tissue samples obtained from colectomies of individuals suffering Here we describe the isolation of stem cells of the human colonic epithelium. Differential cell surface abundance of ephrin type-B receptor 2 (EPHB2) allows the purification of different cell types from human colon mucosa biopsies. The highest EPHB2 surface levels correspond to epithelial colonic cells with the longest telomeres and elevated expression of intestinal stem cell (ISC) marker genes. Moreover, using culturing conditions that recreate the ISC niche, a substantial proportion of EPHB2-high cells can be expanded in vitro as an undifferentiated and multipotent population.
Nature America, Inc. All rights reserved. 01/2011;
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ABSTRACT: Fecal incontinence is highly prevalent, especially in menopausal women. The aim of this study was to analyze the expression of estrogen and progesterone receptors in the anal canal of women in relation to menopausal status and age.
Samples of hemorrhoidal tissue were obtained from 34 women undergoing hemorrhoidectomy. The patients were divided into 2 groups: group 1 consisted of women with a menstrual cycle (n = 17) and group 2 consisted of postmenopausal women (n = 17). Immunostaining of hormone receptors was performed using specific antibodies (DAKO, Copenhagen, Denmark) in cells from the internal anal sphincter, the vascular epithelium, and the squamous epithelium. The percentage of positivity of receptors and the association between age and receptor positivity were compared between the 2 groups.
Estrogen receptors were found in the internal anal sphincter in 23.5% in group 1 vs 11.8% in group 2 (P = .656). Progesterone receptors were found in 41.2% in group 1 vs 11.8% of group 2 (P = .118). Squamous epithelium showed estrogen receptors in 52.9% in group 1 vs 64.7% of group 2 (P = .388) and progesterone receptors in 17.6% and 0% in groups 1 and 2, respectively (P = .227). Vascular endothelium showed no receptors. Receptor positivity was not associated with age.
No significant differences were found in the detection of estrogen and progesterone receptors in structures of the anal canal in women in relation to menopausal status and age.
Diseases of the Colon & Rectum 12/2010; 53(12):1687-91. · 3.13 Impact Factor
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ABSTRACT: A 33-year-old woman who presented with epigastric discomfort and diarrhea underwent an abdominal ultrasound (US). This investigation and subsequent contrast-enhanced computed tomography, magnetic resonance imaging and endoscopic US with fine needle aspiration (FNA) revealed a 40 mm well-circumscribed mass in the uncinate process of the pancreas. Findings were suggestive of a mucinous or solid-cystic pseudopapillary tumor of the pancreas, although other lesions such as a non-functioning neuroendocrine tumor could not be ruled out. FNA samples were negative for malignant cells, but of limited value due to poor cellularity. It was decided to surgically remove the tumor because malignancy could not be discounted. Multiple intraoperative biopsies were suggestive of mesenchymal tumor and consequently a conservative resection (uncinatectomy) was performed. The postoperative course was uneventful. The definitive diagnosis was ganglioneuroma. Immunocytochemistry showed positive staining with vimentin, S-100 protein, neurofilament and neuron-specific enolase. Ganglioneuroma is a rare benign tumor that can also present as a pancreatic tumor. Uncinatectomy is feasible, safe and a good surgical technique for the treatment of non-malignant tumors located in the uncinate process of the pancreas.
World Journal of Gastroenterology 09/2009; 15(34):4334-8. · 2.47 Impact Factor
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Cirugía Española 08/2009; 87(4):257-9. · 0.87 Impact Factor
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ABSTRACT: To investigate the histogenetical unifying theory of a single, pluripotential primitive cell for vulvar angiomyxoma, aggresive angiomyxoma, and angiomyofibroblastoma, an optical, immunohistochemical and ultrastructural study of a superficial angiomyxoma, aggressive angiomyxoma, and angiomyofibroblastoma was performed. These three tumors showed immunohistochemical and ultrastructural overlapping features. The results of the study suggest that these three tumor entities probably arise on a common pluripotential primitive cell located around the vessels of connective tissue, which could show the capacity for modulating its penotype toward similar but distinct mature cell types.
Ultrastructural Pathology 07/2009; 30(3):193-205. · 0.76 Impact Factor
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ABSTRACT: Periodic endoscopic follow-up is recommended after the diagnosis of Barrett's oesophagus, particularly in patients with dysplasia. The new endoscopic techniques show promising results in identifying areas suspected of housing high grade dysplasia and adenocarcinoma. Endoscopic resection of the mucosa has become a fundamental technique for the complete histological assessment of these lesions and is able to establish appropriate therapeutic decisions. Likewise, this technique may be the therapeutic option in patients with high grade dysplasia and adenocarcinoma, although its application must be complemented with ablation techniques such as radiofrequency to eliminate the residual Barrett's metaplasia. Oesophagectomy associated with lymphadenectomy is the option of choice in patients with submucosal adenocarcinoma. The diagnosis and treatment of patients with early onset high grade dysplasia and adenocarcinoma must be carried out with multidisciplinary teams who can evaluate each case individually. This strategy will enable the oesophagus to be preserved in many patients with high grade dysplasia and indicate oesophagectomy in selected cases.
Cirugía Española 07/2009; 85(6):331-40. · 0.87 Impact Factor
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Carles Martínez-Romero,
Ilse Rooman,
Anouchka Skoudy,
Carmen Guerra,
Xavier Molero,
Ana González, Mar Iglesias,
Tania Lobato,
Almudena Bosch,
Mariano Barbacid,
Francisco X Real,
Inmaculada Hernández-Muñoz
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ABSTRACT: Chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC) are associated with major changes in cell differentiation. These changes may be at the basis of the increased risk for PDAC among patients with chronic pancreatitis. Polycomb proteins are epigenetic silencers expressed in adult stem cells; up-regulation of Polycomb proteins has been reported to occur in a variety of solid tumours such as colon and breast cancer. We hypothesized that Polycomb might play a role in preneoplastic states in the pancreas and in tumour development/progression. To test these ideas, we determined the expression of PRC1 complex proteins (Bmi1 and Ring1b) during pancreatic development and in pancreatic tissue from mouse models of disease: acute and chronic pancreatic injury, duct ligation, and in K-Ras(G12V) conditional knock-in and caerulein-treated K-Ras(G12V) mice. The study was extended to human pancreatic tissue samples. To obtain mechanistic insights, Bmi1 expression in cells undergoing in vitro exocrine cell metaplasia and the effects of Bmi1 depletion in an acinar cancer cell line were studied. We found that Bmi1 and Ring1B are expressed in pancreatic exocrine precursor cells during early development and in ductal and islet cells-but not acinar cells-in the adult pancreas. Bmi1 expression was induced in acinar cells during acute injury, in acinar-ductal metaplastic lesions, as well as in pancreatic intraepithelial neoplasia (PanIN) and PDAC. In contrast, Ring1B expression was only significantly and persistently up-regulated in high-grade PanINs and in PDAC. Bmi1 knockdown in cultured acinar tumour cells led to changes in the expression of various digestive enzymes. Our results suggest that Bmi1 and Ring1B are modulated in pancreatic diseases and could contribute differently to tumour development.
The Journal of Pathology 07/2009; 219(2):205-13. · 6.32 Impact Factor
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ABSTRACT: Recent studies suggest potential roles of the endocannabinoid system in gastrointestinal inflammation. Although cannabinoid CB(2) receptor expression is increased in inflammatory disorders, the presence and function of the remaining proteins of the endocannabinoid system in the colonic tissue is not well characterized.
Cannabinoid CB(1) and CB(2) receptors, the enzymes for endocannabinoid biosynthesis DAGLalpha, DAGLbeta and NAPE-PLD, and the endocannabinoid-degradating enzymes FAAH and MAGL were analysed in both acute untreated active ulcerative pancolitis and treated quiescent patients in comparison with healthy human colonic tissue by immunocytochemistry. Analyses were carried out according to clinical criteria, taking into account the severity at onset and treatment received.
Western blot and immunocytochemistry indicated that the endocannabinoid system is present in the colonic tissue, but it shows a differential distribution in epithelium, lamina propria, smooth muscle and enteric plexi. Quantification of epithelial immunoreactivity showed an increase of CB(2) receptor, DAGLalpha and MAGL expression, mainly in mild and moderate pancolitis patients. In contrast, NAPE-PLD expression decreased in moderate and severe pancolitis patients. During quiescent pancolitis, CB(1), CB(2) and DAGLalpha expression dropped, while NAPE-PLD expression rose, mainly in patients treated with 5-ASA or 5-ASA+corticosteroids. The number of immune cells containing MAGL and FAAH in the lamina propria increased in acute pancolitis patients, but dropped after treatment.
Endocannabinoids signaling pathway, through CB(2) receptor, may reduce colitis-associated inflammation suggesting a potential drugable target for the treatment of inflammatory bowel diseases.
PLoS ONE 02/2009; 4(9):e6893. · 4.09 Impact Factor
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ABSTRACT: Over-expression of Snail1 gene transcriptional repressor promotes an epithelial-to-mesenchymal transition in epithelial tumour cell lines. Expression of Snail1 RNA has been associated to the pathogenesis of a number of malignancies; however, the lack of good monoclonal antibodies against this protein has precluded a definitive analysis of Snail1 protein. In this study, we aimed to determine the expression of this transcriptional factor in colorectal tumours. Using a Snail1 well-characterized monoclonal antibody developed in our laboratories we have analyzed by immunohistochemistry a cohort of 162 human colorectal tumours. Ninety tumours (56%) showed nuclear expression in the tumoral tissue and the adjacent stroma; in 34 (21%), Snail1 was detected just in the stroma, whereas in only 4 the expression of Snail1 was detected in the tumoral tissue and the stroma was negative. No correlation was found between the presence of Snail1 in the tumour and tumour stage; however, a trend (p = 0.054) was detected when the expression of this factor in the stroma was considered. Snail1 immunoreactivity in this compartment was associated with presence of distant metastasis (p = 0.006). Moreover, expression of Snail1 in the tumor stroma correlated with lower specific survival of cancer patients (p = 0.011). Interestingly, this correlation was also detected in stage I and II tumors. Therefore, our results indicate that the presence of nuclear Snail1 immunoreactive cells in the stroma may be an informative indicator of prognosis of colon tumours especially useful in those corresponding to lower stages and identify a new marker suitable to label activated stroma in colon tumours.
PLoS ONE 02/2009; 4(5):e5595. · 4.09 Impact Factor
