Identification of Five Candidate Lung Cancer Biomarkers by Proteomics Analysis of Conditioned Media of Four Lung Cancer Cell Lines

Planque, Chris; Kulasingam, Vathany; Smith, Chris; Reckamp, Karen L.; Goodglick, Lee; Diamandis, Eleftherios P.

doi:10.1074/mcp.m900134-mcp200

Cited by 133 publications

(111 citation statements)

References 67 publications

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“…The mechanisms underlying the distinct molecular features observed in ADC-TAFs and SCC-TAFs remain unknown. However, they could be associated with differences in the secretome of cancer cells from these two subtypes (44). Unlike stiff substrata, no marked differences in absolute (not normalized) cell density values were observed in 1 kPa gels between ADC-TAFs and SCC-TAFs ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 97%

Matrix Stiffening and β1 Integrin Drive Subtype-Specific Fibroblast Accumulation in Lung Cancer

Puig

Lugo

Gabasa

et al. 2015

Molecular Cancer Research

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The crucial role of tumor-associated fibroblasts (TAF) in cancer progression is now clear in non-small cell lung cancer (NSCLC). However, therapies against TAFs are limited due to a lack of understanding in the subtype-specific mechanisms underlying their accumulation. Here, the mechanical (i.e., matrix rigidity) and soluble mitogenic cues that drive the accumulation of TAFs from major NSCLC subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SCC) were dissected. Fibroblasts were cultured on substrata engineered to exhibit normal-or tumor-like stiffnesses at different serum concentrations, and critical regulatory processes were elucidated. In control fibroblasts from nonmalignant tissue, matrix stiffening alone increased fibroblast accumulation, and this mechanical effect was dominant or comparable with that of soluble growth factors up to 0.5% serum. The stimulatory cues of matrix rigidity were driven by b1 integrin mechanosensing through FAK (pY397), and were associated with a posttranscriptionally driven rise in b1 integrin expression. The latter mechano-regulatory circuit was also observed in TAFs but in a subtype-specific fashion, because SCC-TAFs exhibited higher FAK (pY397), b1 expression, and ERK1/2 (pT202/Y204) than ADCTAFs. Moreover, matrix stiffening induced a larger TAF accumulation in SCC-TAFs (>50%) compared with ADC-TAFs (10%-20%). In contrast, SCC-TAFs were largely serum desensitized, whereas ADC-TAFs responded to high serum concentration only. These findings provide the first evidence of subtype-specific regulation of NSCLC-TAF accumulation. Furthermore, these data support that therapies aiming to restore normal lung elasticity and/or b1 integrin-dependent mechano regulation may be effective against SCC-TAFs, whereas inhibiting stromal growth factor signaling may be effective against ADC-TAFs.Implications: This study reveals distinct mechanisms underlying the abnormal accumulation of tumor-supporting fibroblasts in two major subtypes of lung cancer, which will assist the development of personalized therapies against these cells.

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Section: Discussionmentioning

confidence: 97%

Matrix Stiffening and β1 Integrin Drive Subtype-Specific Fibroblast Accumulation in Lung Cancer

Puig

Lugo

Gabasa

et al. 2015

Molecular Cancer Research

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“…PTX3 protein or TNF inducible gene 14 encoded by PTX3 gene in humans is secreted by different cell types such as endothelial cells, mononuclear phagocytes, dendritic cells and fibroblasts upon stimulation with primary inflammatory cytokines and toll like receptor engagement. Planque et al [152] found that serum levels of PTX3 were much higher in lung cancer patients (median = 4.91 ng/ml) compared to healthy individuals (median = 1.52 ng/ml). The diagnostic sensitivity of pentraxin at 100% specificity was found to be 68%.…”

Section: Potential Of Lung Cancer Protein Biomarkersmentioning

confidence: 99%

Serum-based protein biomarkers for detection of lung cancer

2014

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Lung cancer is one of the most common cancers in terms of both incidence and mortality.The major reasons for the increasing number of deaths from lung cancer are late detection and lack of effective therapies. To improve our understanding of lung cancer biology, there is urgent need for blood-based, non-invasive molecular tests to assist in its detection in a cost-effective manner at an early stage when curative interventions are still possible. Recent advances in proteomic technology have provided extensive, high throughput analytical tools for identification, characterization and functional studies of proteomes. Changes in protein expression patterns in response to stimuli can serve as indicators or biomarkers of biological and pathological processes as well as physiological and pharmacological responses to drug treatment, thus aiding in early diagnosis and prognosis of disease. However, only a few biomarkers have been approved by the FDA to date for screening and diagnostic purposes. This review provides a brief overview of currently available proteomic techniques, their applications and limitations and the current state of knowledge about important serum biomarkers in lung cancer and their potential value as prognostic and diagnostic tools.

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“…Any of these play key roles in a variety of diseases, including cancer. Aberrant expression of ADAM17 has been shown in various malignancies (17)(18)(19). However, reports on the expression and function of ADAM17 in prostate cancer are limited.…”

Section: Introductionmentioning

confidence: 99%

ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion

Xiao

Lin²,

Lin³

et al. 2011

Int J Oncol

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Abstract. ADAM17, also known as tumor necrosis factor-α converting enzyme (TACE), is involved in proteolytic ectodomain shedding of cell surface molecules and cytokines. Although aberrant expression of ADAM17 has been shown in various malignancies, the function of ADAM17 in prostate cancer has not been clarified. In the present study, we sought to elucidate whether ADAM17 contributes to prostate cancer cell invasion, as well as the mechanism involved in the process. The expression pattern of ADAM17 was investigated in human prostate cancer cells. The results showed that ADAM17 expression levels are correlated with the invasive ability of androgen-independent prostate cancer cell lines. Further, ADAM17 was overexpressed in cells showing high invasion characteristics, activation of the EGFR-MEK-ERK pathway, up-regulation of MMP-2, MMP-9, and an increased TGF-α release into the supernatant. However, AG1478, PD98059 and antibody against TGF-α deactivating the EGFR-MEK-ERK signaling pathway, abolished up-regulation of MMP-2, MMP-9 and prevented cell invasion. In addition, cells with knockdown of ADAM17 by siRNA exhibited low invasive ability, deactivated EGFR-MEK-ERK signaling pathway, reduced TGF-α released and down-regulation of MMP-2, MMP-9. However, these effects could be reversed by simultaneous addition of TGF-α. These data demonstrated that ADAM17 contributes to androgen-independent prostate cancer cell invasion by shedding of EGFR ligand TGF-α, which subsequently activates the EGFR-MEK-ERK signaling pathway, leading finally to overexpression of MMP-2 and MMP-9. This study suggests that the ADAM17 expression level may be a new predictive biomarker of invasion and metastasis of prostate cancer, and ADAM17 could provide a target for treating metastatic PCa. IntroductionProstate cancer (PCa) is one of the most common malignancies among Western males with an occurrence of approximately 192,280 new cases and 27,360 deaths in the US, in 2009 (1). The growth and maintenance of cancerous cells in the early stages of prostate cancer is androgen-dependent and therapy often involves androgen deprivation (2). In the later stages therapeutic alternatives are not available, as the tumor progresses from androgen-dependence to -independence. The lack of effective therapies for advanced PCa is related to a large extent to poor understanding of the molecular mechanisms underlying the progression of disease toward invasion and metastasis (3). Therefore, the identification of new predictive biomarkers, especially those that are indicative of invasiveness of the disease, which could serve as targets for establishing effectiveness of therapeutic and chemopreventive interventions, will improve clinical management of PCa (4).The ADAMs (a disintegrin and metalloproteinase) are members of the metzincin superfamily of Zn-dependent matrix metalloproteinases. They are transmembrane and secreted proteins with important roles in diverse biological functions, such as fertilization, adhesion, migration, proteolysis and signaling (5,6). Recent...

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Identification of Five Candidate Lung Cancer Biomarkers by Proteomics Analysis of Conditioned Media of Four Lung Cancer Cell Lines

Cited by 133 publications

References 67 publications

Matrix Stiffening and β1 Integrin Drive Subtype-Specific Fibroblast Accumulation in Lung Cancer

Matrix Stiffening and β1 Integrin Drive Subtype-Specific Fibroblast Accumulation in Lung Cancer

Serum-based protein biomarkers for detection of lung cancer

ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion

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