Stromal markers of activated tumor associated fibroblasts predict poor survival and are associated with necrosis in non-small cell lung cancer

Alcaraz, Jordi; Carrasco, Josep L.; Millares, Laura; Luis, Iuliana-Cristiana; Fernández-Porras, Francisco J.; Martínez-Romero, Anabel; Díaz-Valdivia, Natalia; Cos, Julio Sánchez de; Rami‐Porta, Ramón; Seijó, Luis; Ramírez, Josep; Pajares, María J.; Reguart, Noemı́; Barreiro, Esther; Monsó, Eduard

doi:10.1016/j.lungcan.2019.07.020

Cited by 39 publications

(42 citation statements)

References 48 publications

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“…Furthermore, blockade of Shh production by cancer cells inhibited CAF proliferation yet accelerated PDAC progression in mice, leading to the speculation that α‐SMA + rCAF may proliferate in response to Shh signaling . However, multiple studies have revealed a correlation between the number of α‐SMA + CAF and poor outcomes in various types of human solid cancers, leading to the opposing hypothesis that states that α‐SMA + CAF are a type of pCAF that shape a tumor‐permissive and tumor‐promoting environment . In addition, there is ongoing discussion regarding the roles of α‐SMA + CAF in tumor immunity.…”

Section: Meflin: a Candidate Marker Of Cancer‐restraining Cancer‐assomentioning

confidence: 99%

Cancer‐associated fibroblasts that restrain cancer progression: Hypotheses and perspectives

et al. 2020

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The roles of cancer-associated fibroblasts (CAF) in the progression of various types of cancers are well established. CAF promote cancer progression through pleiotropic mechanisms, including the secretion of soluble factors and extracellular matrix, physical interactions with cancer cells, and the regulation of angiogenesis, immunity and metabolism. Their contribution to therapeutic resistance is also well appreciated. Therefore, CAF have been considered as a therapeutic target in cancer. However, recent studies in autochthonous pancreatic cancer models suggest that specific subset(s) of CAF exhibit cancer-restraining roles, indicating that CAF are functionally and molecularly heterogeneous, which is supported by recent single-cell transcriptome analyses. While cancer-promoting CAF (pCAF) have been extensively studied, the nature and specific marker(s) of cancer-restraining CAF (rCAF) have remained uncharacterized. Interestingly, a recent study provided insight into the nature of rCAF and suggested that they may share molecular properties with pancreatic stellate cells (PSC) and mesenchymal stem/stromal cells (MSC). Complicating this finding is that PSC and MSC have been shown to promote the formation of a tumor-permissive and tumor-promoting environment in xenograft tumor models. However, these cells undergo significant transcriptional and epigenetic changes during ex vivo culture, which confounds the interpretation of experimental results based on the use of cultured cells. In this short review, we describe recent studies and hypotheses on the identity of rCAF and discuss their analogy to fibroblasts that suppress fibrosis in fibrotic diseases. Finally, we discuss how these findings can be exploited to develop novel anticancer therapies in the future. K E Y W O R D Scancer-restraining cancer-associated fibroblasts, fibrosis, Meflin, mesenchymal stem/stromal cells, tumor microenvironment

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Section: Meflin: a Candidate Marker Of Cancer‐restraining Cancer‐assomentioning

confidence: 99%

Cancer‐associated fibroblasts that restrain cancer progression: Hypotheses and perspectives

et al. 2020

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“…Histochemical (van Gieson staining, Picro-Sirius red, etc.) and immunohistochemical techniques are routinely used to stain fibrillar collagens ( 198 – 200 ). These techniques require additional fixation and preparation steps, which can alter the collagen structure of the samples, and hence are limited to ex vivo materials.…”

Section: Imaging Fibrillar Collagensmentioning

confidence: 99%

“…Images of stained samples are obtained using bright-field, polarized and fluorescence microscopy techniques ( 199 , 200 ). Laser scanning microscopes or multiphoton laser scanning microscopes have also been used to visualize stained tissues in three dimensions ( 198 ).…”

Section: Imaging Fibrillar Collagensmentioning

confidence: 99%

Reciprocal Interplay Between Fibrillar Collagens and Collagen-Binding Integrins: Implications in Cancer Progression and Metastasis

et al. 2020

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Cancers are complex ecosystems composed of malignant cells embedded in an intricate microenvironment made of different non-transformed cell types and extracellular matrix (ECM) components. The tumor microenvironment is governed by constantly evolving cell-cell and cell-ECM interactions, which are now recognized as key actors in the genesis, progression and treatment of cancer lesions. The ECM is composed of a multitude of fibrous proteins, matricellular-associated proteins, and proteoglycans. This complex structure plays critical roles in cancer progression: it functions as the scaffold for tissues organization and provides biochemical and biomechanical signals that regulate key cancer hallmarks including cell growth, survival, migration, differentiation, angiogenesis, and immune response. Cells sense the biochemical and mechanical properties of the ECM through specialized transmembrane receptors that include integrins, discoidin domain receptors, and syndecans. Advanced stages of several carcinomas are characterized by a desmoplastic reaction characterized by an extensive deposition of fibrillar collagens in the microenvironment. This compact network of fibrillar collagens promotes cancer progression and metastasis, and is associated with low survival rates for cancer patients. In this review, we highlight how fibrillar collagens and their corresponding integrin receptors are modulated during cancer progression. We describe how the deposition and alignment of collagen fibers influence the tumor microenvironment and how fibrillar collagen-binding integrins expressed by cancer and stromal cells critically contribute in cancer hallmarks.

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“…In the 2015 World Health Organization Classification of Lung Cancer, the presence of CAF is an indicator of invasion in earlystage LUAD (2). Stromal markers of activated CAF have been proved to predict poor prognosis in non-small cell lung cancer including adenocarcinoma (30). A previous study indicated that CAF could promote the invasion of LUAD cells by remodeling extracellular matrix (31).…”

Section: By Guest On December 6 2020mentioning

confidence: 99%

Proteomic Analyses Identify Differentially Expressed Proteins and Pathways Between Low-Risk and High-Risk Subtypes of Early-Stage Lung Adenocarcinoma and Their Prognostic Impacts

Zhou

Liu

et al. 2021

Molecular & Cellular Proteomics

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The histopathological subtype of lung adenocarcinoma (LUAD) is closely associated with prognosis. Micropapillary or solid predominant LUAD tends to relapse after surgery at an early stage, whereas lepidic pattern shows a favorable outcome. However, the molecular mechanism underlying this phenomenon remains unknown. Here, we recruited 31 lepidic predominant LUADs (LR: low-risk subtype group) and 28 micropapillary or solid predominant LUADs (HR: high-risk subtype group). Tissues of these cases were obtained and label-free quantitative proteomic and bioinformatic analyses were performed. Additionally, prognostic impact of targeted proteins was validated using The Cancer Genome Atlas databases (n=492) and tissue microarrays composed of early-stage LUADs (n=228). A total of 192 differentially expressed proteins were identified between tumor tissues of LR and HR and three clusters were identified via hierarchical clustering excluding eight proteins. Cluster 1 (65 proteins) showed a sequential decrease in expression from normal tissues to tumor tissues of LR and then to HR and was predominantly enriched in pathways such as tyrosine metabolism and ECM-receptor interaction, and increased matched mRNA expression of 18 proteins from this cluster predicted favorable prognosis. Cluster 2 (70 proteins) demonstrated a sequential increase in expression from normal tissues to tumor tissues of LR and then to HR and was mainly enriched in pathways such as extracellular organization, DNA replication and cell cycle, and high matched mRNA expression of 25 proteins indicated poor prognosis. Cluster 3 (49 proteins) showed high expression only in LR, with high matched mRNA expression of 20 proteins in this cluster indicating favorable prognosis. Furthermore, high expression of ERO1A and FEN1 at protein level predicted poor prognosis in early-stage LUAD, supporting the mRNA results. In conclusion, we discovered key differentially expressed proteins and pathways between low-risk and high-risk subtypes of early-stage LUAD. Some of these proteins could serve as potential biomarkers in prognostic evaluation.

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Stromal markers of activated tumor associated fibroblasts predict poor survival and are associated with necrosis in non-small cell lung cancer

Cited by 39 publications

References 48 publications

Cancer‐associated fibroblasts that restrain cancer progression: Hypotheses and perspectives

Cancer‐associated fibroblasts that restrain cancer progression: Hypotheses and perspectives

Reciprocal Interplay Between Fibrillar Collagens and Collagen-Binding Integrins: Implications in Cancer Progression and Metastasis

Proteomic Analyses Identify Differentially Expressed Proteins and Pathways Between Low-Risk and High-Risk Subtypes of Early-Stage Lung Adenocarcinoma and Their Prognostic Impacts

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