A gene signature of cancer-associated fibroblasts predicts prognosis and treatment response in bladder cancer

Objective Due to the pivotal role cancer-associated fibroblasts (CAFs) play in tumor progression, our study aimed to develop a signature of CAFs-related gene (CRG) to predict the survival outcomes and treatment response of bladder cancer (BLCA). Methods The transcriptome data and relevant clinical information about BLCA were collected from publicly available databases, including The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Weighted gene co-expression network analysis was utilized to uncover CAFs-associated hub genes, and subsequently, a risk model for survival prognosis was constructed using LASSO-Cox regression. The immune microenvironment, immune infiltration, immunotherapy response, and drug sensitivity were explored using ESTIMATE, CIBERSORT, TIDE, and oncoPredict algorithms. To verify the expression of the CRGs, additional analyses were performed using online databases (HPA, CCLE, TIMER, cBioPortal, and TISCH). Results Our study developed a CRG signature and constructed a prognostic model. Significant differences in overall survival were observed between the two risk stratifications. The risk score increased with the infiltration of CAFs and tumor staging progression, while closely correlating with immune checkpoint expression and infiltration of CD8 T cells, follicular helper T cells, regulatory T cells, activated dendritic cells, M0 macrophages, M2 macrophages, and resting mast cells. Furthermore, a higher proportion of patients in the low-risk stratification exhibited responsiveness to immunotherapy, and significant variances in sensitivity to multiple chemotherapy medications were observed between the two risk stratifications. Conclusion The construction of the risk model based on the CRG signature offers new avenues for the prognosis evaluation and development of personalized treatment strategies for BLCA (AU)

El papel del microambiente tumoral y los fibroblastos asociados a cáncer en el desarrollo y la progresión del cáncer de mama / The role of tumor microenvironment and cancer-associated fibroblasts in breast cancer development and progression

Es bien sabido que el cáncer mamario es considerado un problema de salud a nivel mundial, la enorme tasa de mortalidad se debe a la recaída de la enfermedad, principalmente por la generación de resistencia a los diversos tratamientos. Hasta hace unos años, esta resistencia era atribuida a las mutaciones genéticas heredadas, sin embargo, evidencias recientes sugieren que el microambiente tumoral desempeña un papel clave en el desarrollo y la progresión del cáncer. La relación simbiótica entre las células tumorales y los fibroblastos asociados a cáncer (FAC), condicionan un ambiente propicio para el soporte estructural necesario, lleno de nutrientes que favorecen su crecimiento y progresión. Aquí se describe el papel que juega el microambiente tumoral y los FAC, desde su origen celular y activación, hasta los mecanismos de quimiorresistencia tumoral, además de los cambios epigenéticos y las proteínas involucradas, como las HDAC, que prometen ser blancos terapéuticos de nuevos fármacos dirigidos a su inhibición, al mitigar diversas vías que participan en la activación de los FAC o revertir su potencial promotor de tumores, lo que a su vez, mejoraría la calidad de vida de las pacientes. (AU)

It is well known that breast cancer is considered a worldwide health problem, the enormous mortality rate is due to the relapse of patients mostly due to the generation of resistance to various treatments. Until a few years ago, this resistance was attributed to inherited genetic mutations, however, recent evidence suggests that tumor microenvironment plays a key role in the development and progression of cancer. The symbiotic relationship between tumor cells and cancer-associated fibroblasts (CAF) provides an environment conducive to the necessary structural support, full of nutrients that favor their growth and progression. Here we describe the role played by the tumor microenvironment and CAF, from their cellular origin and activation to the mechanisms of tumor chemoresistance, in addition to the epigenetic changes and proteins involved, such as HDAC, which promise to be therapeutic targets for new drugs aimed at their inhibition, by mitigating various pathways involved in the activation of CAF or reversing their tumor-promoting potential, which in turn, would improve the quality of life of patients. (AU)

Cancer-associated fibroblasts contribute to cancer metastasis and apoptosis resistance in human ovarian cancer via paracrine SDF-1a

Background Cancer-associated fibroblasts (CAFs), one of the main members of stromal cells in tumor microenvironment are proposed to play a central role in promoting tumor metastasis. It is unclear whether and how CAFs mediates tumor metastasis or chemoresistance in human ovarian cancer. Methods CAFs were extracted from human ovarian cancer tissues (OCs) of patients with different kinds of histological types. Results We found that CAFs showed more aggressive potency than those tumor cells, both of which were isolated from the same ovarian cancer specimen. Moreover, when co-cultured with CAFs, cell migration abilities of ovarian cancer cells (SKOV3, OVCAR3 and HEY) were significantly increased. Next, we preliminarily detected a higher CAFs density in sections of metastatic lesions than those in primary tumor site of primary OCs clinically. However, no significant difference of stromal derived factors-1α (SDF-1α) production from CAFs was found between primary and metastatic lesions. Additionally, in contrast with tumor cells, CAFs exhibited obvious apoptosis resistance when treated with cisplatin. Furthermore, we found that cisplatin-induced cytotoxicity and apoptosis were significantly inhibited by co-cultured with recombinant human SDF-1α in SKOV3 in a time and dose-dependent manner, and this effect was suppressed by the CXCR4 antagonist AMD3100. Conclusions CAFs might be involved in the malignant metastasis in human ovarian cancer through promoting cell migration in tumor cells. And their resistance to cytotoxic agents might be mediated by paracrine SDF-1α/CXCR4 signaling in ovarian cancer (AU)

The role of microRNAs in the modulation of cancer-associated fibroblasts activity during pancreatic cancer pathogenesis

Pancreatic ductal adenocarcinoma (PDAC) is the deadliest of the common cancers. A major hallmark of PDAC is an abundant and dense fibrotic stroma, the result of a disproportionate deposition of extracellular matrix (ECM) proteins. Cancer-associated fibroblasts (CAFs) are the main mediators of PDAC desmoplasia. CAFs represent a heterogenous group of activated fibroblasts with different origins and activation mechanisms. microRNAs (miRNAs) are small non-coding RNAs with critical activity during tumour development and resistance to chemotherapy. Increasing evidence has revealed that miRNAs play a relevant role in the differentiation of normal fibroblasts into CAFs in PDAC. In this review, we discuss recent findings on the role of miRNAs in the activation of CAFs during the progression of PDAC and its response to therapy, as well as the potential role that PDAC-derived exosomal miRNAs may play in the activation of hepatic stellate cells (HSCs) and formation of liver metastasis. Since targeting of CAF activation may be a viable strategy for PDAC therapy, and miRNAs have emerged as potential therapeutic targets, understanding the biology underpinning miRNA-mediated tumour cell-CAF interactions is an important component in guiding rational approaches to treating this deadly disease. (AU)

Stroma-targeting strategies in pancreatic cancer: a double-edged sword

Pancreatic ductal adenocarcinoma (PDAC) is a type of cancer with limited treatment options and terrible long-term survival, and it is expected to become the second leading cause of cancer-related death by 2030. One reason why this cancer is so aggressive and resistant is the formation of dense stroma that surrounds the neoplastic epithelium, which promotes tumor progression, invasion, metastasis, and resistance. The three major components of PDAC stroma are extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), and vasculature. The dense ECM acts as a natural physical barrier, impeding drug penetration to PDAC tumor cells. Consequently, the method that combines stroma-targeting with anticancer therapy may be a viable alternative for increasing drug penetration. Additionally, blood vessels are key entities of the tumor stroma, serving as a pathway for nutrition as well as the only way for chemical medicines and immune cells to act. Finally, PDAC CAFs and tumor cells have crosstalk effects in the tumor microenvironment, where they are responsible for enhanced matrix deposition. In this review, we aim to provide an overview of our current comprehension of the three key components of PDAC stroma and the new promising therapeutic targets for PDAC. (AU)

Inclusion of cancer-associated fibroblasts in drug screening assays to evaluate pancreatic cancer resistance to therapeutic drugs

Pancreatic ductal adenocarcinoma (PDAC) is characterised by a pro-inflammatory stroma and multi-faceted microenvironment that promotes and maintains tumorigenesis. However, the models used to test new and emerging therapies for PDAC have not increased in complexity to keep pace with our understanding of the human disease. Promising therapies that pass pre-clinical testing often fail in pancreatic cancer clinical trials. The objective of this study was to investigate whether changes in the drug-dosing regimen or the addition of cancer-associated fibroblasts (CAFs) to current existing models can impact the efficacy of chemotherapy drugs used in the clinic. Here, we reveal that gemcitabine and paclitaxel markedly reduce the viability of pancreatic cell lines, but not CAFs, when cultured in 2D. Following the use of an in vitro drug pulsing experiment, PDAC cell lines showed sensitivity to gemcitabine and paclitaxel. However, CAFs were less sensitive to pulsing with gemcitabine compared to their response to paclitaxel. We also identify that a 3D co-culture model of MIA PaCa-2 or PANC-1 with CAFs showed an increased chemoresistance to gemcitabine when compared to standard 2D mono-cultures a difference to paclitaxel which showed no measurable difference between the 2D and 3D models, suggesting a complex interaction between the drug in study and the cell type used. Changes to standard 2D mono-culture-based assays and implementation of 3D co-culture assays lend complexity to established models and could provide tools for identifying therapies that will match clinically the success observed with in vitro models, thereby aiding in the discovery of novel therapies. (AU)

Oxaliplatin inhibits colorectal cancer progression by inhibiting CXCL11 secreted by cancer-associated fibroblasts and the CXCR3/PI3K/AKT pathway

Purpose Colorectal cancer (CRC) is a malignant tumor. Oxaliplatin (OXA) can inhibit cancer-associated fibroblasts (CAFs)-induced cancer progression. This study sought to explore the mechanism of OXA in CAFs-induced CRC development. Methods CRC cell lines (Caco-2, SW620), normal fibroblasts (NFs), and CAFs were treated with OXA. NFs and CAFs were cultured. CAFs were treated with/without OXA (0.4 mM), and the supernatant was extracted as the conditioned medium (CM) to culture CRC cells. Cell malignant episodes, E-cadherin and Vimentin levels, CXCL1, CXCL2, CXCL3, CXCL8, and CXCL11 mRNA levels, CXCL11 protein level, and extracellular release were assessed. CAFs were transfected with interfering RNA sh-CXCL11 to silence CXCL11 or transfected with CXCL11 overexpression plasmids and treated with OXA to explore the role of CXCL11 in OXA-mediated CRC cells through CAFs. CXCL11 receptor CXCR3 levels in CRC cells and the PI3K/AKT pathway changes were examined. The xenogeneic tumor was transplanted in nude mice. CXCL11 and CXCR3 levels in tumor tissues, tumor volume, shape, size, weight, and Ki67 positive expressions were assessed. Results CRC cell growths and epithelial–mesenchymal transformation were stimulated after culture with CAFs–CM, while OXA averted these trends. CXCL11 mRNA level was elevated most significantly, and its protein and extracellular secretion levels were raised, while OXA diminished the levels. CXCL11 silencing weakened the effects of CAFs–CM on promoting CRC proliferation and malignant episodes and CXCL11 overexpression averted OXA property on inhibiting CAFs-promoted CRC cell growth (AU)

Cancer-associated fibroblasts in colorectal cancer

Colorectal cancer (CRC) is one of the leading causes of mortality among cancers. Many aspects of this cancer are under investigation to find established markers of diagnosis, prognosis, and also potential drug targets. In this review article, we are going to discuss the possible solution to all these aims by investigating the literature about cancer-associated fibroblasts (CAFs) involved in CRC. Moreover, we are going to review their interaction with the tumor microenvironment (TME) and vitamin D and their role in tumorigenesis and metastasis. Moreover, we are going to expand more on some markers produced by them or related to them including FAP, a-SMA, CXCL12, TGF- β, POSTN, and β1-Integrin. Some signaling pathways related to CAFs are as follows: FAK, AKT, activin A, and YAP/TAZ. Some genes related to the CAFs which are found to be possible therapeutic targets include COL3A1, JAM3, AEBP1 and, CAF-derived TGFB3, WNT2, and WNT54.

Markers of Stroma in Lung Cancer: Influence of COPD / Marcadores estromales en el cáncer de pulmón: la influencia de la enfermedad pulmonar obstructiva crónica

BACKGROUND: Stroma, mainly composed by fibroblasts, extracellular matrix (ECM) and vessels, may play a role in tumorigenesis and cancer progression. Chronic Obstructive Pulmonary Disease (COPD) is an independent risk factor for LC. We hypothesized that markers of fibroblasts, ECM and endothelial cells may differ in tumors of LC patients with/without COPD. METHODS: Markers of cultured cancer-associated fibroblasts and normal fibroblasts [CAFs and NFs, respectively, vimentin and alpha-smooth muscle actin (SMA) markers, immunofluorescence in cultured lung fibroblasts], ECM, and endothelial cells (type I collagen and CD31 markers, respectively, immunohistochemistry) were identified in lung tumor and non-tumor specimens (thoracotomy for lung tumor resection) from 15 LC-COPD patients and 15 LC-only patients. RESULTS: Numbers of CAFs significantly increased, while those of NFs significantly decreased in tumor samples compared to non-tumor specimens of both LC and LC-COPD patients. Endothelial cells (CD31) significantly decreased in tumor samples compared to non-tumor specimens only in LC patients. No significant differences were seen in levels of type I collagen in any samples or study groups. CONCLUSIONS: Vascular endothelial marker CD31 expression was reduced in tumors of non-COPD patients, while type I collagen levels did not differ between groups. A rise in CAFs levels was detected in lung tumors of patients irrespective of airway obstruction. Low levels of CD31 may have implications in the overall survival of LC patients, especially in those without underlying airway obstruction. Identification of CD31 role as a prognostic and therapeutic biomarker in lung tumors of patients with underlying respiratory diseases warrants attention

ANTECEDENTES: El estroma, compuesto principalmente por fibroblastos, matriz extracelular (MEC) y vasos, puede desempeñar un papel en la génesis tumoral y la progresión del cáncer. La enfermedad pulmonar obstructiva crónica (EPOC) es un factor de riesgo independiente para el carcinoma de pulmón (CP). Nuestra hipótesis fue que los marcadores de fibroblastos, MEC y células endoteliales pueden variar en los tumores de los pacientes con CP con o sin EPOC. MÉTODOS: Se identificaron los marcadores de fibroblastos asociados al cáncer y los fibroblastos normales cultivados (FAC y FN, respectivamente; marcadores: vimentina y α-actina del músculo liso [SMA por sus siglas en inglés]; inmunofluorescencia en fibroblastos de pulmón cultivados) y marcadores de la MEC y las células endoteliales (marcadores: colágeno tipo I y CD31, respectivamente; inmunohistoquímica) en muestras de pulmón tumoral y no tumoral (toracotomía para resección de tumores pulmonares) de 15 pacientes con EPOC-CP y 15 pacientes con solo CP. RESULTADOS: El número de FAC aumentó de forma significativa, mientras que el de FN disminuyó significativamente en las muestras tumorales en comparación con las muestras no tumorales de pacientes con CP y EPOC-CP. Las células endoteliales (CD31) disminuyeron también de forma significativa en las muestras tumorales en comparación con las muestras no tumorales solo en los pacientes con CP. No se observaron diferencias significativas en los niveles de colágeno tipo I en ninguna muestra o grupo de estudio. CONCLUSIONES: La expresión del marcador vascular endotelial CD31 se redujo en los tumores de los pacientes sin EPOC, mientras que los niveles de colágeno tipo I no difirieron entre los grupos. Se detectó un aumento en los niveles de FAC en los tumores de pulmón de los pacientes, con independencia de la presencia de obstrucción de las vías respiratorias. Los niveles bajos de CD31 pueden tener implicaciones en la supervivencia general de los pacientes con CP, en especial, en aquellos sin obstrucción subyacente de las vías respiratorias. Convendría estudiar e identificar el papel del CD31 como biomarcador terapéutico y de pronóstico en los tumores de pulmón de pacientes con enfermedades respiratorias subyacentes

Immunohistochemical analysis of cancer-associated fibroblasts and podoplanin in head and neck cancer

BACKGROUND: To immunohistochemically evaluate the association between the presence of cancer-associated fibroblasts (CAFs) and the tumour expression of podoplanin (PDPN) in head and neck squamous cell carcinoma (HNSCC) and their association with clinicopathological variables. MATERIAL AND METHODS: A tissue microarray (TMA) with biopsy sections from patients diagnosed with HNSCC was stained with antibodies against the CAFs marker, α-smooth muscle actin (α-SMA), and PDPN. We subsequently evaluated their expression to determine the association between them and with clinicopathological variables including age, primary tumour site, TNM stage, and tumour differentiation grade. RESULTS: Positive reaction to α-SMA was observed in the tumour stroma, revealing spindle-shaped cells compatible with CAFs, which showed a high expression in 62% of cases and a significant association with laryngeal carcinomas, advanced clinical stages, and lower tumour differentiation (P ≤ 0.05). PDPN staining on tumour cells showed low expression in 72% of cases, and it was not associated with any clinicopathological variable or with the presence of CAFs. CONCLUSIONS: The presence of CAFs in the tumour stroma is related to an aggressive phenotype and could increase as the disease progresses, although based on our findings, it would have no relationship, at least directly, with the expression of PDPN

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Characterization of tumor-derived mesenchymal stem cells potentially differentiating into cancer-associated fibroblasts in lung cancer

Purpose: The goal of this study was to understand if mesenchymal stem cells isolated from lung tumor tissue (T-MSCs) may differentiate into cancer associated fibroblasts (CAFs), that promote neoplastic progression, angiogenesis and metastasis in the epithelial solid tumors, mimicking the tumor microenvironmental influence. Methods: MSCs were been obtained from healthy (Control, C-MSCs) and tumor (T-MSCs) tissue of one patient who underwent a lobectomy for a lung adenocarcinoma pT1bN0. Isolated cells were characterized for the presence of molecular markers (identified by routine diagnostic characterization in differentiated tumoral cells), stemness properties, and CAF-related markers expression. Subsequently, cells were co-cultured with a lung adenocarcinoma cell line (A549 cells) to evaluate the effects on proliferation, oncogene expression and IL6 secretion. Results: C- and T-MSCs did not present EGFR mutations unlike tumor tissue and showed a stem-like immunophenotype, characterized by the ability to differentiate towards osteo-, chondro- and adipogenic lineages. The expression of markers referred to CAFs (alfa-SMA, HI-1alfa, MMP11, VEGF, CXCL12, TGF-Beta1, TGF-BetaRII, IL6, TNFalfa) was significantly higher in T-MSCs than in C-MSCs. The co-cultures with A549 cells led to the over-expression of selected oncogenes and to the increase of IL6 secretion in T-MSCs but not in C-MSCs. Conclusions: MSCs isolated from tumor tissue displayed distinct properties compared to MSCs isolated from healthy tissue, suggesting T-MSCs differentiation towards a CAF-related phenotype under the influence of the tumoral microenvironment

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Elastofibroma dorsal bilateral: hallazgos en PET/TC / Bilateral elastofibroma dorsi: PET-CT findings

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