The malignity of lung cancer is conditioned by the tumor microenvironment (TME), in which cancer-associated fibroblasts (CAFs) are relevant. In this work, we generated organoids by combining A549 ...cells with CAFs and normal fibroblasts (NF) isolated from adenocarcinoma tumors. We optimized the conditions for their manufacture in a short time. We evaluated the morphology of organoids using confocal microscopy analysis of F-actin, vimentin and pankeratin. We determined the ultrastructure of the cells in the organoids via transmission electron microscopy and the expression of CDH1, CDH2 and VIM via RT-PCR. The addition of stromal cells induces the self-organization of the organoids, which acquired a bowl morphology, as well as their growth and the generation of cell processes. They also influenced the expression of genes related to epithelial mesenchymal transition (EMT). CAFs potentiated these changes. All cells acquired a characteristic secretory phenotype, with cohesive cells appearing inside the organoids. In the periphery, many cells acquired a migratory phenotype, especially in organoids that incorporated CAFs. The deposit of abundant extracellular matrix could also be observed. The results presented here reinforce the role of CAFs in the progression of lung tumors and could lay the foundation for a useful in vitro pharmacological model.
There is evidence that demonstrates the effect of cannabinoid agonists inhibiting relevant aspects in lung cancer, such as proliferation or epithelial-to-mesenchymal transition (EMT). Most of these ...studies are based on evidence observed in in vitro models developed on cancer cell lines. These studies do not consider the complexity of the tumor microenvironment (TME). One of the main components of the TME is cancer-associated fibroblasts (CAFs), cells that are relevant in the control of proliferation and metastasis in lung cancer. In this work, we evaluated the direct effects of two cannabinoid agonists, tetrahydrocannabinol (THC) and cannabidiol (CBD), used alone or in combination, on CAFs and non-tumor normal fibroblasts (NFs) isolated from adenocarcinoma or from healthy lung tissue from the same patients. We observed that these compounds decrease cell density in vitro and inhibit the increase in the relative expression of type 1 collagen (COL1A1) and fibroblast-specific protein 1 (FSP1) induced by transforming growth factor beta (TGFβ). On the other hand, we studied whether THC and CBD could modulate the interactions between CAFs or NFs and cancer cells. We conditioned the culture medium with stromal cells treated or not with THC and/or CBD and cultured A549 cells with them. We found that culture media conditioned with CAFs or NFs increased cell density, induced morphological changes consistent with EMT, inhibited cadherin-1 (CDH1) gene expression, and induced an increase in the relative expression of cadherin-2 (CDH2) and vimentin (VIM) genes in A549 cells. These changes were inhibited or decreased by THC and CBD administered alone or in combination. In another series of experiments, we conditioned culture media with A549 cells treated or not with THC and/or CBD, in the presence or absence of TGFβ. We observed that culture media conditioned with A549 in the presence of TGFβ induced an increase in the expression of COL1A1 and VIM, both in CAFs and in non-tumor NFs. Both THC and CBD ameliorated these effects. In summary, the results presented here reinforce the usefulness of cannabinoid agonists for the treatment of some relevant aspects of lung cancer pathology, and demonstrate in a novel way their possible effects on CAFs as a result of their relationship with cancer cells. Likewise, the results reinforce the usefulness of the combined use of THC and CBD, which has important advantages in relation to the possibility of using lower doses, thus minimizing the psychoactive effects of THC.
Lung cancer (LC) is a major public health issue. Despite recent advances in treatment, primary prevention and early diagnosis are key to reducing the incidence and mortality of this disease. A recent ...clinical trial demonstrated the efficacy of selective screening by low-dose computed tomography (LDCT) in reducing the risk of both lung cancer mortality and all-cause mortality in high-risk individuals.
This article contains the reflections of an expert group on the use of LDCT for early diagnosis of LC in high-risk individuals, and how to evaluate its implementation in Spain. The expert group was set up by the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), the Spanish Society of Thoracic Surgery (SECT), the Spanish Society of Radiology (SERAM) and the Spanish Society of Medical Oncology (SEOM).
El cáncer de pulmón (CP) constituye un problema de salud pública de primer orden. A pesar de los recientes avances en su tratamiento, la prevención primaria y el diagnóstico precoz son las claves para reducir su incidencia y mortalidad. Un ensayo clínico reciente demostró la eficacia del cribado selectivo con tomografía computarizada de baja dosis (TCBD) en la reducción del riesgo de muerte en personas de alto riesgo, tanto por CP como global.
Este artículo recoge las reflexiones de un grupo de expertos designados por la Sociedad Española de Neumología y Cirugía Torácica (SEPAR), la Sociedad Española de Cirugía Torácica (SECT), la Sociedad Española de Radiología Médica (SERAM) y la Sociedad Española de Oncología Médica (SEOM) sobre el uso de la TCBD para el diagnóstico precoz del CP en personas con riesgo elevado de padecerlo y los pasos necesarios para evaluar su implementación en nuestro país.
The fibrotic tumor microenvironment is a pivotal therapeutic target. Nintedanib, a clinically approved multikinase antifibrotic inhibitor, is effective against lung adenocarcinoma (ADC) but not ...squamous cell carcinoma (SCC). Previous studies have implicated the secretome of tumor-associated fibroblasts (TAFs) in the selective effects of nintedanib in ADC, but the driving factor(s) remained unidentified. Here we examined the role of tissue inhibitor of metalloproteinase-1 (TIMP-1), a tumor-promoting cytokine overproduced in ADC-TAFs. To this aim, we combined genetic approaches with in vitro and in vivo preclinical models based on patient-derived TAFs. Nintedanib reduced TIMP-1 production more efficiently in ADC-TAFs than SCC-TAFs through a SMAD3-dependent mechanism. Cell culture experiments indicated that silencing TIMP1 in ADC-TAFs abolished the therapeutic effects of nintedanib on cancer cell growth and invasion, which were otherwise enhanced by the TAF secretome. Consistently, co-injecting ADC cells with TIMP1-knockdown ADC-TAFs into immunocompromised mice elicited a less effective reduction of tumor growth and invasion under nintedanib treatment compared to tumors bearing unmodified fibroblasts. Our results unveil a key mechanism underlying the selective mode of action of nintedanib in ADC based on the excessive production of TIMP-1 in ADC-TAFs. We further pinpoint reduced SMAD3 expression and consequent limited TIMP-1 production in SCC-TAFs as key for the resistance of SCC to nintedanib. These observations strongly support the emerging role of TIMP-1 as a critical regulator of therapy response in solid tumors.
INTRODUCTIONThe most suitable treatment in most early-stage lung cancer patients is surgical resection. Despite previously assessing each patient's status being relevant to detect possible ...complications inherent to surgery, no consensus has been reached on which factors are "high risk" in such patients. Our study aimed to analyse the morbidity and the mortality incidence associated with this surgery in our setting with a multicentre study and to detect risk parameters. METHODSA prospective analysis study with 3,307 patients operated for bronchopulmonary carcinoma in 24 hospitals. Study variables were age, TNM, gender, stage, smoking habit, surgery approach, surgical resection, ECOG, neoadjuvant therapy, comorbidity, spirometric values, and intraoperative and postoperative morbidity and mortality. A multivariate logistic regression analysis of the morbidity and mortality predictor factors was done. RESULTSWe recorded 34.2% postoperative morbidity and 2.1% postoperative mortality. Gender, myocardial infarction, angina, ECOG ≥1, COPD, DLCO <60%, clinical pathological status, surgical resection and surgery approach were shown as morbidity and mortality predictor factors in lung cancer surgery in our series. CONCLUSIONSThe main variables to consider when assessing the lung cancer patients to undergo surgery are gender, myocardial infarction, angina, ECOG, COPD, DLCO, clinical pathological status, surgical resection and surgery approach.
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