Fibroblast subsets in non-small cell lung cancer: Associations with survival, mutations, and immune features (original) (raw)
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Proceedings of the National Academy of Sciences, 2011
The tumor microenvironment strongly influences cancer development, progression, and metastasis. The role of carcinoma-associated fibroblasts (CAFs) in these processes and their clinical impact has not been studied systematically in non-small cell lung carcinoma (NSCLC). We established primary cultures of CAFs and matched normal fibroblasts (NFs) from 15 resected NSCLC. We demonstrate that CAFs have greater ability than NFs to enhance the tumorigenicity of lung cancer cell lines. Microarray gene-expression analysis of the 15 matched CAF and NF cell lines identified 46 differentially expressed genes, encoding for proteins that are significantly enriched for extracellular proteins regulated by the TGF-β signaling pathway. We have identified a subset of 11 genes (13 probe sets) that formed a prognostic gene-expression signature, which was validated in multiple independent NSCLC microarray datasets. Functional annotation using protein-protein interaction analyses of these and published cancer stroma-associated gene-expression changes revealed prominent involvement of the focal adhesion and MAPK signaling pathways. Fourteen (30%) of the 46 genes also were differentially expressed in laser-capture-microdissected corresponding primary tumor stroma compared with the matched normal lung. Six of these 14 genes could be induced by TGF-β1 in NF. The results establish the prognostic impact of CAF-associated gene-expression changes in NSCLC patients.
Scientific Reports, 2021
Cancer-associated fibroblasts (CAFs) participate in critical processes in the tumor microenvironment, such as extracellular matrix remodeling, reciprocal signaling interactions with cancer cells and crosstalk with infiltrating inflammatory cells. However, the relationships between CAFs and survival are not well known in lung cancer. The aim of this study was to reveal the correlations of CAFs with survival rates, genetic alterations and immune activities. This study reviewed the histological features of 517 patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA) database. We performed gene set enrichment analysis (GSEA), network-based analysis and survival analysis based on CAFs in four histological types of lung adenocarcinoma: acinar, papillary, micropapillary and solid. We found four hallmark gene sets, the epithelial-mesenchymal transition, angiogenesis, hypoxia, and inflammatory response gene sets, that were associated with the presence of CAFs. CAFs were associat...
OMICS: A Journal of Integrative Biology
Solid tumors have complex biology and structure comprising cancer cells, stromal cells, and the extracellular matrix. While most therapeutics target the cancer cells, recent data suggest that cancer cell behavior and response to treatment are markedly influenced by the tumor microenvironment (TME). In particular, the cancerassociated fibroblasts (CAFs) are the most abundant stromal cells, and play a significant contextual role in shaping tumor initiation, progression, and metastasis. CAFs have therefore emerged as part of the nextgeneration cancer drug design and discovery innovation strategy. We report here new findings on differential expression and prognostic significance of CAF markers in several cancers. We utilized two publicly available resources: The Cancer Genomic Atlas and Gene Expression Profiling Interactive Analysis. We examined the expression of CAF markers, ACTA2, S100A4, platelet-derived growth factor receptor-beta [PDGFR-b], CD10, and fibroblast activation protein-alpha (FAP-a), in tumor tissues versus the adjacent normal tissues. We found that CAF markers were differentially expressed in various different tumors such as colon, breast, and esophageal cancers and melanoma. No CAF marker is expressed in the same pattern in all cancers, however. Importantly, we report that patients with colon adenocarcinoma and esophageal carcinoma expressing high FAP-a and CD10, respectively, had significantly shorter overall survival, compared with those with low levels of these CAF markers (p < 0.05). We call for continued research on TME biology and clinical evaluation of the CAF markers ACTA2, S100A4, PDGFR-b, CD10, and FAP-a in relation to prognosis of solid cancers in large population samples. An effective cancer drug design and discovery roadmap in the 21st century ought to be broadly framed, and include molecular targets informed by both cancer cell and TME variations.
Cellular and Molecular Profiling of Tumor Microenvironment and Early-Stage Lung Cancer
International Journal of Molecular Sciences
Lung cancers are broadly divided into two categories: non-small-cell lung carcinoma (NSCLC), which accounts for 80–85% of all cancer cases, and small-cell lung carcinoma (SCLC), which covers the remaining 10–15%. Recent advances in cancer biology and genomics research have allowed an in-depth characterization of lung cancers that have revealed new therapy targets (EGFR, ALK, ROS, and KRAS mutations) and have the potential of revealing even more biomarkers for diagnostic, prognostic, and targeted therapies. A new source of biomarkers is represented by non-coding RNAs, especially microRNAs (miRNAs). MiRNAs are short non-coding RNA sequences that have essential regulatory roles in multiple cancers. Therefore, we aim to investigate the tumor microenvironment (TME) and miRNA tumor profile in a subset of 51 early-stage lung cancer samples (T1 and T2) to better understand early tumor and TME organization and molecular dysregulation. We analyzed the immunohistochemistry expression of CD4 an...
PLOS ONE
Objectives Selective targeting of cancer-associated fibroblasts (CAFs) has been proposed to synergize with immune-checkpoint inhibitors. While the roles of CAFs in cancer development are well described, their immune-regulatory properties remain incompletely understood. This study investigates correlations between CAF and immune-markers in tumor stroma from nonsmall cell lung cancer (NSCLC) patients, and examines whether a combination of CAF and immune cell scores impact patient prognosis. Methods Tumor specimens from 536 primary operable stage I-III NSCLC patients were organized in tissue microarrays. Expression of protein-markers was evaluated by immunohistochemistry. Results Fibroblast and stromal markers PDGFRα, PDGFRβ, FAP-1 and vimentin showed weak correlations while αSMA, and Masson's trichrome did not correlate with any of the investigated markers. Hierarchical clustering indicated the existence of different CAF-subsets. No relevant correlations were found between any CAF-marker and the immune-markers CD3, CD4, CD8, CD20, CD68, CD1a, CD56, FoxP3 and CD45RO. High density of fibroblast-activation protein positive mesenchymal cells (CAF FAP) was associated with better prognosis in tumors with high infiltration of CD8 and CD3 T-lymphocytes. Conclusions The presented data suggest that CAFs, irrespective of identity, have low influence on the degree of tumor infiltration by inflammatory-and/or immune-cells. However, CAF FAP may
OMICS: A Journal of Integrative Biology, 2020
Current therapeutic strategies targeting cancer cells within solid tumors have displayed limited success owing to the presence of non-cancer components referred to as the tumor stroma within the tumor microenvironment (TM). These stromal cells, extracellular matrix and blood vessels influence cancer cell response to therapy and play key roles in tumor relapse and resistance. Of the stromal cells present in the TM, a lot of attention has been given to cancerassociated fibroblasts (CAFs) as they are the most abundant and are important in cancer initiation, progression and therapy resistance. In this updated review I emphasize the role of CAFs in the regulation of tumor cell behaviour and reveal how CAF-derived factors and signaling influence tumor cell heterogeneity and development of novel strategies to combat cancer. To investigate the expression of CAF markers in tumor tissues versus normal tissues, transcriptomic data from The Cancer Genome Atlas (TCGA) and the Gene Expression Profiling Interactive Analysis (GEPIA) databases was used. Bioinformatic analysis reveals differential expression of CAF markers in several cancer types, underscoring the need for further multiomics and biochemical studies on CAFs, CAF subsets and markers. Differences in CAF markers' expression could be due to different cellular origins as well as the effect of cancer-specific tumor microenvironmental effect on CAFs. Lastly, I present recent advances in therapeutic targeting of CAFs and the success of such endeavours or its lack thereof. It is recommended that for patients' outcomes to improve, cancer treatment be combinatorial in nature, targeting both cancer cells and stromal cells and interactions.
Editorial: Impact of tumor microenvironment on lung cancer
Frontiers in Oncology
Editorial on the Research Topic Impact of tumor microenvironment on lung cancer Lung cancer is the leading cause of cancer-related mortality worldwide. In 2022 the Cancer Statistics Center calculated an estimated four new cases and one death per minute from lung cancer solely in the United States (http://cancerstatisticscenter.cancer.org). Lung cancer displays poor survival rates caused by recurrence and metastatic spreading. The anatomical and cellular features of healthy lungs that serve respiratory and defensive purposes, restructure during carcinogenesis to give rise to the tumor microenvironment (TME). This tumor-intermingled "organ" that acts in symbiosis with the cancer cells nourishes their aggressiveness and resistance (1), thus representing a target-rich milieu to hunt for anticancer options. Despite major efforts the complex pro-tumorigenic interactions occurring within the TME landscape (2, 3) are still substantially uncharted, thus precluding design of thoroughly eradicating strategies. Therefore, research must sturdily focus on discovering biomarkers to facilitate early diagnoses, improve clinical predictions and stratification parameters, as well as identifying new avenues to target cancer cells vulnerabilities and to modulate the protumorigenic TME. Within the TME, the immune infiltrating system and the stromal cells have emerged as therapeutic, diagnostic and prognostic tools in NSCLC (4-6). In this Research Topic, several novel biomarker signatures were presented, contributing to the ever-growing puzzle describing the entire complexity of pulmonary TMEs. A 14-TMErelated gene signature was identified to exhibit significant prognostic potential for patients affected by malignant pleural mesothelioma (MPMs), a rare but highly aggressive thoracic malignancy [Xu et al.]. Similarly, analyses from 450 NSCLC cases identified key immune cell types associated with recurrence of stage IA-B NSCLC within 40 months after surgical resection, contributing to develop an immune-related gene panel that predicts relapse-free survival (RFS) [Wang et al.]. Focusing on the immune-related genes differentially expressed in lung adenocarcinomas (LuADs) displaying high and low immune/stromal scores, Colony-stimulating factor 2 receptor beta (CSF2RB) was identified as a hub gene within LuAD-TMEs [Zhu et al.]. Low CSF2RB expression was associated with poor survival and CSF2RB was identified as an independent risk factor for prognosis, independent of whether patients received chemotherapy or radiotherapy. More importantly, a high expression of CSF2RB was related to early T, N, and clinical stages. Further studies are expected to Frontiers in Oncology frontiersin.org 01
Oncology Letters, 2021
Non-small cell lung cancer (NSCLC) is a malignant tumor with high morbidity and mortality rates, which seriously endangers human health. Although treatment methods continue to evolve, the emergence of drug resistance is inevitable and seriously hinders the treatment of NSCLC. The tumor microenvironment (TME) protects tumor cells from the effects of chemotherapeutic drugs, which can lead to drug resistance. Cancer-associated fibroblasts (CAFs) are an important component of the TME, and various studies have demonstrated that CAFs play a crucial role in drug resistance in NSCLC. However, the drug resistance mechanism of CAFs and whether CAFs can be used as a target to reverse the resistance of tumor cells remain unclear. The present review discusses this issue and describes the heterogeneity of CAF markers, as well as their origins and resident organs, and the role and mechanism of this heterogeneity in NSCLC progression. Furthermore, the mechanism of CAF-mediated NSCLC resistance to chemotherapy, targeted therapy and immunotherapy is introduced, and strategies to reverse this resistance are described. Contents 1. Introduction 2. Heterogeneity of CAFs 3. Roles and mechanisms of CAFs in NSCLC drug resistance 4. Therapeutic strategies 5. Conclusions
IntroductionCancer associated fibroblast (CAF) mediated crosstalk with other tumor compartments is shown to modulate cancer development and progression. Conventionally, CAFs are known to promote tumorigenesis either by secreting a wide range of growth factors, cytokines, and chemokines or by remodeling the underlying stroma. However, recent studies aimed at depleting CAFs have shown progression to more aggressive tumors leading to poorer outcomes. This may be attributed to the heterogeneity and plasticity of CAFs. Understanding CAF heterogeneity has been limited due to the lack of specific markers. Imaging mass cytometry (IMC) can analyze up to 40 parameters at subcellular resolution simultaneously and hence it can be an ideal tool to unravel the heterogeneity of CAFs and decipher the role of various CAF subsets in cancer development and progression. The aim of this study was to develop a panel of antibodies (ABs) for IMC to identify different CAF phenotypes and their spatial distri...
European Journal of Cardio-Thoracic Surgery, 2020
OBJECTIVES Tumour-infiltrating lymphocytes (TILs) are critically implicated in the clinical outcome and response to immunotherapy in non-small-cell lung cancer (NSCLC) patients. The functional competence of lymphocyte subpopulations is strongly conditioned by their spatial arrangement within the tumour immune microenvironment. The aim of this study was to determine whether the tissue localization of specific TIL subpopulations might have an impact on the risk of recurrence in surgically resected NSCLC. METHODS High-speed scanning of whole slide images was performed on immunohistochemically stained tissue sections from 97 NSCLC patients to assess the number and ratio of CD3+, CD8+ and PD-1+ T-lymphocytes. TIL distribution was computed considering the intratumoural (proximal or distal) and peripheral (invasive margin) localization as well as their location within the fibrotic tissue (immune excluded). The tumour proliferative index was assessed by Ki67 labelling. The impact of TILs nu...