Proteomic approach to improve the diagnosis of malignant pleural effusions

Comunicaciones a congreso

In the search of early stages biomarkers for non small cell lung cancer

Comunicaciones a congreso

Highly sensitive marker panel for guidance in lung cancer rapid diagnostic units

While evidence for lung cancer screening implementation in Europe is awaited, Rapid Diagnostic Units have been established in many hospitals to accelerate the early diagnosis of lung cancer. We seek to develop an algorithm to detect lung cancer in a symptomatic population attending such unit, based on a sensitive serum marker panel. Serum concentrations of Epidermal Growth Factor, sCD26, Calprotectin, Matrix Metalloproteinases −1, −7, −9, CEA and CYFRA 21.1 were determined in 140 patients with respiratory symptoms (lung cancer and controls with/without benign pathology). Logistic Lasso regression was performed to derive a lung cancer prediction model, and the resulting algorithm was tested in a validation set. A classification rule based on EGF, sCD26, Calprotectin and CEA was established, able to reasonably discriminate lung cancer with 97% sensitivity and 43% specificity in the training set, and 91.7% sensitivity and 45.4% specificity in the validation set. Overall, the panel identified with high sensitivity stage I non-small cell lung cancer (94.7%) and 100% small-cell lung cancers. Our study provides a sensitive 4-marker classification algorithm for lung cancer detection to aid in the management of suspicious lung cancer patients in the context of Rapid Diagnostic Units.Ministerio de Ciencia e Innovación | Ref. PS09-00405Xunta de Galicia | Ref. INBIOMED 2012-273Xunta de Galicia | Ref. GRC2014/019Ministerio de Ciencia e Innovación | Ref. MTM2011-2320

Strategy for the identification of the tumor intrinsic QTL determining the response to treatment of ERBB2 breast cancer

Resumen del póster presentado al VII Simposium Bases Biológicas del Cáncer y Terapias Personalizadas, celebrado en el Centro de Investigación del Cáncer (CIC-IBMCC) del 21 al 22 de mayo de 2015.-- et al.Este póster ha ganado el 1er premio en el Concurso de Pósters de Oncología Básica y Traslacional en Oncología para Jóvenes Investigadores, celebrado durante el VII Simposium Bases Biológicas del Cáncer y Terapias Personalizadas.An essential aspect of breast cancer is its different evolution among patients with the same histopathological disease. Moreover, cancer is a tissue growing in the context of a complex organism, thus it can be identified two main sources of variability responsible for the disease behavior: intrinsic and extrinsic factors which act, respectively, mainly inside the tumor cells and outside them at local or systemic levels. Our aim is to identify intrinsic factors to the tumor cells responsible for the different responses of breast cancer to chemotherapy with Doxorubicin and Docetaxel. For this purpose, we collected tumors developed in a cohort of genetically heterogeneous mice from a backcross between a resistant strain to breast cancer (C57BL/6) and a susceptible one (FVB) which overexpress the cNeu/ErbB2 protooncogene controlled by the MMTV promoter. The backcross mice were genotyped by SNP analysis. To identify tumor intrinsic factors controlling the response to chemotherapy, we transplanted 125 tumors collected from the backcross mice into singenic F1-C57/FVB mice to remove variability coming from the host compartments. Each tumor was transplanted into two F1 recipient mice; each one was treated with Doxorubicin or Docetaxel, and we studied tumor response to treatment. Linkage analysis permits us to identify QTL (Quantitative Trait Loci) controlling susceptibility to mammary cancer and evolution of the disease in the backcross population, and the specific intrinsic QTL associated with different chemotherapy responses in the F1 mice. Moreover, we are studying molecular and signalling pathways that control chemotherapy responses and the QTL associated with them. The identification of breast cancer susceptibility genes and their pathways associated with different response to chemotherapy will be important for the prediction of human breast cancer evolution during therapy, and to learn about the mechanisms involved in resistance to chemotherapy, thus it would help to develop new preventive and therapeutic strategies.Peer Reviewe

A new role of SNAI2 in postlactational involution of the mammary gland links it to luminal breast cancer development

PMCID: PMC4560637Breast cancer is a major cause of mortality in women. The transcription factor SNAI2 has been implicated in the pathogenesis of several types of cancer, including breast cancer of basal origin. Here we show that SNAI2 is also important in the development of breast cancer of luminal origin in MMTV-ErbB2 mice. SNAI2 deficiency leads to longer latency and fewer luminal tumors, both of these being characteristics of pretumoral origin. These effects were associated with reduced proliferation and a decreased ability to generate mammospheres in normal mammary glands. However, the capacity to metastasize was not modified. Under conditions of increased ERBB2 oncogenic activity after pregnancy plus SNAI2 deficiency, both pretumoral defects - latency and tumor load - were compensated. However, the incidence of lung metastases was dramatically reduced. Furthermore, SNAI2 was required for proper postlactational involution of the breast. At 3 days post lactational involution, the mammary glands of Snai2-deficient mice exhibited lower levels of pSTAT3 and higher levels of pAKT1, resulting in decreased apoptosis. Abundant noninvoluted ducts were still present at 30 days post lactation, with a greater number of residual ERBB2+ cells. These results suggest that this defect in involution leads to an increase in the number of susceptible target cells for transformation, to the recovery of the capacity to generate mammospheres and to an increase in the number of tumors. Our work demonstrates the participation of SNAI2 in the pathogenesis of luminal breast cancer, and reveals an unexpected connection between the processes of postlactational involution and breast tumorigenesis in Snai2-null mutant mice.JPL was partially supported by FEDER and MICINN (PLE2009-119, SAF2014-56989-R), Instituto de Salud Carlos III (PI07/0057, PI10/00328, PIE14/00066), Junta de Castilla y León (SAN673/SA26/08, SAN126/SA66/09, SA078A09, CSI034U13), the “Fundación Eugenio Rodríguez Pascual”, the “Fundación Inbiomed” (Instituto Oncológico Obra Social de la Caja Guipozcoa-San Sebastian, Kutxa), and the “Fundación Sandra Ibarra de Solidaridad frente al Cáncer”. AC was supported by FIS (PI07/0057) and MICINN (PLE2009-119). SCLL was funded by a JAEdoc Fellowship (CSIC)/FSE. MMSF and ABG are funded by fellowships from the Junta de Castilla y Leon. JHM was supported by the National Institutes of Health, a National Cancer Institute grant (R01 CA116481), and the Low-Dose Scientific Focus Area, Office of Biological & Environmental Research, US Department of Energy (DE-AC02-05CH11231).Peer Reviewe

The biological age linked to oxidative stress modifies breast cancer aggressiveness

The incidence of breast cancer increases with age until menopause, and breast cancer is more aggressive in younger women. The existence of epidemiological links between breast cancer and aging indicates that both processes share some common mechanisms of development. Oxidative stress is associated with both cancer susceptibility and aging. Here we observed that ERBB2-positive breast cancer, which developed in genetically heterogeneous ERBB2-positive transgenic mice generated by a backcross, is more aggressive in chronologically younger than in older mice (differentiated by the median survival of the cohort that was 79 weeks), similar to what occurs in humans. In this cohort, we estimated the oxidative biological age using a mathematical model that integrated several subphenotypes directly or indirectly related to oxidative stress. The model selected the serum levels of HDL-cholesterol and magnesium and total AKT1 and glutathione concentrations in the liver. The grade of aging was calculated as the difference between the predicted biological age and the chronological age. This comparison permitted the identification of biologically younger and older mice compared with their chronological age. Interestingly, biologically older mice developed more aggressive breast cancer than the biologically younger mice. Genomic regions on chromosomes 2 and 15 linked to the grade of oxidative aging were identified. The levels of expression of Zbp1 located on chromosome 2, a gene related to necroptosis and inflammation, positively correlated with the grade of aging and tumour aggressiveness. Moreover, the pattern of gene expression of genes linked to the inflammation and the response to infection pathways was enriched in the livers of biologically old mice. This study shows part of the complex interactions between breast cancer and aging.JPL was partially supported by FEDER and the MICINN (SAF2014-56989-R and SAF2017-88854R), the Instituto de Salud Carlos III (PIE14/00066), >Proyectos Integrados IBSAL 2015> (IBY15/00003), the Sandra Ibarra Foundation >de Solidaridad Frente al Cáncer> Foundation and >We can be heroes> Foundation. JHM was supported by the National Institutes of Health, a National Cancer Institute grant (R01 CA116481), and the Low-Dose Scientific Focus Area, Office of Biological & Environmental Research, US Department of Energy (DE-AC02-05CH11231).Peer Reviewe

The Spectrum of Interstitial Lung Disease Associated With Autoimmune Diseases: Data of a 3.6-Year Prospective Study From a Referral Center of Interstitial Lung Disease and Lung Transplantation

Interstitial lung disease (ILD) may occur in patients with a rheumatic autoimmune disease (AD), increasing their risk of morbidity and mortality. However, little is known about the prevalence of AD in patients diagnosed with an ILD. In this prospective study, we determined the spectrum of ILD associated with AD (AD-ILD) among patients sent for assessment to a single clinic of ILD and lung transplantation from a referral center between May 2016 and December 2019. ILD diagnosis was made by pneumologists based on clinical and radiological findings and pulmonary function test abnormalities. All patients with ILD were also assessed by experienced rheumatologists. During the period of assessment, 338 patients were diagnosed with ILD. Among them, 32.8% fulfilled definitions for an AD. Most cases with AD-ILD had a diagnosis of rheumatoid arthritis (27.0%), systemic sclerosis (26.1%) or anti-synthetase syndrome (17.1%). Interestingly, 18% of the patients with AD-ILD were diagnosed as having an interstitial pneumonia with autoimmune features. Antinuclear antibodies and non-specific interstitial pneumonia were the most frequent positive autoantibodies and radiological pattern found in AD-ILD patients, respectively. In conclusion, our study indicates that a high number of ILD patients have a related AD. Consequently, close collaboration among rheumatologists and pneumologists is needed.This research received no external funding. SR-M is supported by funds of the RETICS Program (RD16/0012/0009) (Instituto de Salud Carlos III, co-funded by the European Regional Development Fund)

Unraveling heterogeneous susceptibility and the evolution of breast cancer using a systems biology approach

This is an Open Access article distributed under the terms of the Creative Commons Attribution License.-- et al.[Background]: An essential question in cancer is why individuals with the same disease have different clinical outcomes. Progress toward a more personalized medicine in cancer patients requires taking into account the underlying heterogeneity at different molecular levels. [Results]: Here, we present a model in which there are complex interactions at different cellular and systemic levels that account for the heterogeneity of susceptibility to and evolution of ERBB2-positive breast cancers. Our model is based on our analyses of a cohort of mice that are characterized by heterogeneous susceptibility to ERBB2-positive breast cancers. Our analysis reveals that there are similarities between ERBB2 tumors in humans and those of backcross mice at clinical, genomic, expression, and signaling levels. We also show that mice that have tumors with intrinsically high levels of active AKT and ERK are more resistant to tumor metastasis. Our findings suggest for the first time that a site-specific phosphorylation at the serine 473 residue of AKT1 modifies the capacity for tumors to disseminate. Finally, we present two predictive models that can explain the heterogeneous behavior of the disease in the mouse population when we consider simultaneously certain genetic markers, liver cell signaling and serum biomarkers that are identified before the onset of the disease. [Conclusions]: Considering simultaneously tumor pathophenotypes and several molecular levels, we show the heterogeneous behavior of ERBB2-positive breast cancer in terms of disease progression. This and similar studies should help to better understand disease variability in patient populations.JPL was partially supported by FEDER and MICINN (PLE2009-119), FIS (PI07/0057, PI10/00328, PIE14/00066), the Junta de Castilla y León (SAN673/SA26/08; SAN126/SA66/09, SA078A09, CSI034U13), the “Fundación Eugenio Rodríguez Pascual”, the Fundación Inbiomed (Instituto Oncológico Obra Social de la Caja Guipozcoa-San Sebastian, Kutxa), and the “Fundación Sandra Ibarra de Solidaridad frente al Cáncer”. AC was supported by MICINN (PLE2009-119). SCLL is funded by a JAEdoc Fellowship (CSIC)/FSE. MMSF and ABG are funded by fellowships from the Junta de Castilla y Leon. WR was supported by a Forschungsstipendium of the Deutsche Forschungsgemeinschaft (DFG) [RE 3108/1-1]. TN, BPB and DYL acknowledge support from the US Department of Energy Low-Dose SFA Program at Berkeley Lab [DE-AC02-05CH11231], the National Institutes of Health [RC1NS069177] and the California Breast Cancer Research Program [15IB-0063]. JHM was supported by the National Institutes of Health, a National Cancer Institute grant (R01 CA116481), and the Low-Dose Scientific Focus Area, Office of Biological and Environmental Research, US Department of Energy (DE-AC02-05CH11231).Peer Reviewe