Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer (original) (raw)
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Oncogene, 2003
Increasing evidence supports a major role for the microenvironment in carcinoma formation and progression. The influence of the stroma is partly mediated by signalling between epithelial tumor cells and neighboring fibroblasts. However, the molecular mechanisms underlying these interactions are largely unknown. To mimic the initial steps of invasive carcinoma in which tumor cells come in contact with normal stromal cells, we used a coculture model of non-small-cell lung cancer tumor cells and normal pulmonary fibroblasts. Using DNA filter arrays, we first analysed the overall modification of gene expression profile after a 24 h period of coculture. Next, we focused our interest on the transcriptome of the purified fibroblastic fraction of coculture using both DNA filter arrays and a laboratory-made DNA microarray. These experiments allowed the identification of a set of modulated genes coding for growth and survival factors, angiogenic factors, proteases and protease inhibitors, transmembrane receptors, kinases and transcription regulators that can potentially affect the regulation of matrix degradation, angiogenesis, invasion, cell growth and survival. This study represents to our knowledge the first attempt to dissect early global gene transcription occurring in a tumor-stroma coculture model and should help to understand better some of the molecular mechanisms involved in heterotypic signalling between epithelial tumor cells and fibroblasts.
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...
2023
Skrzypski et al-3-gene signature in squamous cell carcinoma of the lung Supplemental Documents Supplemental Text S1 Genes identified as prognostic markers in the univariate analysis The other seven genes also identified as predictors of survival in the univariate analysis are related to cell adhesion, cell motility, cell proliferation and angiogenesis. PH-4 is a novel HIF-1α prolyl hydroxylase that is involved in the degradation of HIF under normoxia 1 and was found to be selectively overexpressed in squamous cell carcinoma by microarrays 2. Our study corroborated that PH-4 overexpression significantly correlates with shorter survival. Functionally, its overexpression results in downregulation of HIF-1α and CA IX, which is in line with the negative impact on prognosis of low CA IX expression. FN was identified in a six-gene expression signature as predicting survival in diffuse large-B-cell lymphoma 3. FN, an extracellular matrix glycoprotein highly expressed in tobacco-related lung disease, stimulates lung cancer growth. By binding to the integrin α5β1 receptor, FN stimulates the expression of MMP-9 through the activation of c-Fos protein and the ERK and PI3K signaling pathways. This induces MMP-9 gene transcription, which promotes tumor invasion, proliferation and metastasis 4. Although in our study expression of FN significantly correlated with survival, no such correlation was observed for MMP-9. Both tumor-and host-derived MMPs contribute to multiple stages of tumor progression through their ability to degrade the basement membrane and components of the extracellular matrix 5. Lack of host MMP-9 reduced Lewis lung cancer nodules in syngenic mice and in A549 cells in immunocompromised mice. Intriguingly, host MMP-9 contributes to the early stages of tumors but has no effect on subsequent tumor growth 5. By complexing MMP-9 with CD44, transforming growth factor β is activated 6. It has been suggested that selectins participate in the initial tethering of circulating tumor cells to host organ endothelium 7. Selectins are vascular cell-cell adhesion receptors that usually bind to certain sialyl Lewis-containing mucin-type glycoproteins found in normal leukocytes and endothelium. Selectin-L is constitutively expressed in
Cancer-associated Fibroblasts: Origins, Heterogeneity and Functions in Tumor Microenvironment
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 cancer-associated 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 Pr...
Anticancer research, 2013
The metastatic potential of non-small cell lung cancer (NSCLC) cells has been shown to be associated with the tumor microenvironment. Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment, regulating tumor cell function by secreting growth factors, chemokines, and extracellular matrix (ECM). In this study, we examined the role of CAFs in the tumor progression of NSCLC. Firstly, we established primary cultures of CAFs and matched normal fibroblasts (NFs) from patients with resected NSCLC. CAFs exhibited greater expression of the pan-mesenchymal marker α-smooth muscle actin (α-SMA) than did NFs, although they displayed similar morphology. Furthermore, we employed a direct co-culture assay with human NSCLC A549 and H358 cells, and found that CAFs were more potent in inducing the epithelial-to-mesenchymal transition (EMT) phenotype than NFs, as indicated by an elongated and disseminated appearance. CAF-induced EMT led to an increase in motility and a d...
JNCI: Journal of the National Cancer Institute
Background Cancer-associated fibroblasts (CAFs) are molecularly heterogeneous mesenchymal cells that interact with malignant cells and immune cells and confer anti- and protumorigenic functions. Prior in situ profiling studies of human CAFs have largely relied on scoring single markers, thus presenting a limited view of their molecular complexity. Our objective was to study the complex spatial tumor microenvironment of non-small cell lung cancer (NSCLC) with multiple CAF biomarkers, identify novel CAF subsets, and explore their associations with patient outcome. Methods Multiplex fluorescence immunohistochemistry was employed to spatially profile the CAF landscape in 2 population-based NSCLC cohorts (n = 636) using antibodies against 4 fibroblast markers: platelet-derived growth factor receptor-alpha (PDGFRA) and -beta (PDGFRB), fibroblast activation protein (FAP), and alpha-smooth muscle actin (αSMA). The CAF subsets were analyzed for their correlations with mutations, immune chara...
The Role of Cancer-Associated Fibroblasts in Tumor Progression
Cancers
In the era of genomic medicine, cancer treatment has become more personalized as novel therapeutic targets and pathways are identified. Research over the past decade has shown the increasing importance of how the tumor microenvironment (TME) and the extracellular matrix (ECM), which is a major structural component of the TME, regulate oncogenic functions including tumor progression, metastasis, angiogenesis, therapy resistance, and immune cell modulation, amongst others. Within the TME, cancer-associated fibroblasts (CAFs) have been identified in several systemic cancers as critical regulators of the malignant cancer phenotype. This review of the literature comprehensively profiles the roles of CAFs implicated in gastrointestinal, endocrine, head and neck, skin, genitourinary, lung, and breast cancers. The ubiquitous presence of CAFs highlights their significance as modulators of cancer progression and has led to the subsequent characterization of potential therapeutic targets, whic...
Exploring the tumour environment: cancer-associated fibroblasts as targets in cancer therapy
Expert Opinion on Therapeutic Targets, 2005
Stroma cells contribute to the microenvironment that is essential for cancer growth, invasion and metastatic progression. Fibroblasts, often termed myofibroblasts or cancer-associated fibroblasts (CAFs), represent the most abundant cell type in the tumour stroma. The demonstrated tumour-promoting capacities of CAFs has increased the interest to exploit them as drug targets for anticancer therapy. Although single factors, such as platelet-derived growth factor, transforming growth factor-β1, hepatocyte growth factor and matrix metalloproteinases have been identified as mediators in the fibroblast tumour interaction, the morphological and functional differences of CAFs compared with their normal counterparts are only incompletely understood. Recently, novel global methods for gene expression profiling were applied to comprehensively characterise CAFs from breast, pancreas, colon and basal cell cancer in their in situ environment. The analysis of different CAF preparations revealed regulated genes that were previously not described in the tumourstroma context. Additionally, besides a few striking overlaps, the comparison of the gene lists indicates a high level of heterogeneity in the expression pattern of CAFs from different tumour types. Together, these studies emphasise the importance of cross-talk between stromal and malignant cells of the tumour. It is likely that the continued characterisation of this interaction, and the molecular identification of key mediators, will provide insights into tumour biology and suggest novel therapeutic options.
Proceedings of the National Academy of Sciences, 2007
Integrin ␣11 (ITGA11/␣11) is localized to stromal fibroblasts and commonly overexpressed in non-small-cell lung carcinoma (NSCLC). We hypothesized that stromal ␣11 could be important for the tumorigenicity of NSCLC cells. SV40 immortalized mouse embryonic fibroblasts established from wild-type (WT) and Itga11deficient [knockout (KO)] mice were tested for their tumorigenicity in immune-deficient mice when implanted alone or coimplanted with the A549 human lung adenocarcinoma cells. A549 coimplanted with the fibroblasts showed a markedly enhanced tumor growth rate compared with A549, WT, or KO, which alone formed only small tumors. Importantly, the growth was significantly greater for A549؉WT compared with A549؉KO tumors. Reexpression of human ␣11 cDNA in KO cells rescued a tumor growth rate to that comparable with the A549؉WT tumors. These findings were validated in two other NSCLC cell lines, NCI-H460 and NCI-H520. Gene expression profiling indicated that IGF2 mRNA expression level was >200 times lower in A549؉KO compared with A549؉WT tumors. Stable short-hairpin RNA (shRNA) down-regulation of IGF2 in WT (WT shIGF2) fibroblasts resulted in a decreased growth rate of A549؉WTshIGF2, compared with A549؉WT tumors. The results indicate that ␣11 is an important stromal factor in NSCLC and propose a paradigm for carcinoma-stromal interaction indirectly through interaction between the matrix collagen and stromal fibroblasts to stimulate cancer cell growth.
Transcriptional Profiling of Non-small Cell Lung Cancer Using Oligonucleotide Microarrays*
CHEST Journal, 2002
Background. Activating somatic mutations in epidermal growth factor receptor (EGFR) confer unique biologic features to nonsmall cell lung cancer (NSCLC) cells, but the transcriptional mediators of EGFR in this subgroup of NSCLC have not been fully elucidated. Methodology/Principal Findings. Here we used genetic and pharmacologic approaches to elucidate the transcriptomes of NSCLC cell lines. We transcriptionally profiled a panel of EGFR-mutant and -wild-type NSCLC cell lines cultured in the presence or absence of an EGFR tyrosine kinase inhibitor. Hierarchical analysis revealed that the cell lines segregated on the basis of EGFR mutational status (mutant versus wild-type), and expression signatures were identified by supervised analysis that distinguished the cell lines based on mutational status (wild-type versus mutant) and type of mutation (L858R versus D746-750). Using an EGFR mutation-specific expression signature as a probe, we mined the gene expression profiles of two independent cohorts of NSCLC patients and found the signature in a subset. EGFR tyrosine kinase inhibitor treatment regulated the expression of multiple genes, and pharmacologic inhibition of the protein products of two of them (PTGS2 and EphA2) inhibited anchorage-independent growth in EGFR-mutant NSCLC cells. Conclusions/Significance. We have elucidated genes not previously associated with EGFR-mutant NSCLC, two of which enhanced the clonogenicity of these cells, distinguishing these mediators from others previously shown to maintain cell survival. These findings have potential clinical relevance given the availability of pharmacologic tools to inhibit the protein products of these genes.