Prediction of Recurrence-Free Survival in Postoperative Non–Small Cell Lung Cancer Patients by Using an Integrated Model of Clinical Information and Gene Expression

Lee, Eung-Sirk; Son, Dae‐Soon; Kim, Sung-Hyun; Lee, Jinseon; Jo, Jaemin; Han, Joungho; Kim, Heesue; Lee, Hyun Joo; Choi, Hye Young; Jung, Youngja; Park, Miyeon; Lim, Yu Sung; Kim, Kwhanmien; Shim, Young Mog; Kim, Byung Chul; Lee, Kyusang; Huh, Nam; Ko, Christopher; Park, Kyunghee; Lee, Jae Won; Choi, Yong Soo; Kim, Young Tae

doi:10.1158/1078-0432.ccr-07-4937

Cited by 233 publications

(253 citation statements)

References 46 publications

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“…Datasets used for prognostic signature discovery and validation were the adenocarcinoma (ADC) dataset from the DCC (n = 442) (10) and NSCLC datasets from Duke University (n = 89) (12) and SKKU (n = 138) (13). Six cases in the DCC with either unknown adjuvant treatment (adjuvant chemo therapy or radiation therapy) or unknown stage were excluded.…”

Section: Methodsmentioning

confidence: 99%

Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer

Navab

Strumpf

Bandarchi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

321

302

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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.integrin α11 | NAViGaTOR | adenocarcinoma | extracellular matrix

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Section: Methodsmentioning

confidence: 99%

Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer

Navab

Strumpf

Bandarchi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

321

302

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“…21 We used the criteria of false discovery rate o0.1 and log 2 fold change 41.5 or o − 1.5. To evaluate the relationship between LAMC2 mRNA expression level and prognosis in NSCLC, we used three publicly available mRNA microarray data: the first cohort of 204 ADCs from Japanese National Cancer Center (JNCC set; HG-U133A Plus 2.0; GSE31210), 46 the second cohort of a mix of 63 ADCs and 75 SCCs from the Samsung Medical Center (SMC set; HG-U133A Plus 2.0; GSE8894), 47 and the third cohort of 59 ADCs and 52 SCCs from Duke University Medical Center (DUMC set; HG-U133A Plus 2.0; GSE3141). 48 Detailed methods were described in the Supplementary section.…”

Section: Methodsmentioning

confidence: 99%

LAMC2 enhances the metastatic potential of lung adenocarcinoma

et al. 2015

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Lung cancer is the number one cancer killer, and metastasis is the main cause of high mortality in lung cancer patients. However, mechanisms underlying the development of lung cancer metastasis remain unknown. Using genome-wide transcriptional analysis in an experimental metastasis model, we identified laminin γ2 (LAMC2), an epithelial basement membrane protein, to be significantly upregulated in lung adenocarcinoma metastatic cells. Elevated LAMC2 increased traction force, migration, and invasion of lung adenocarcinoma cells accompanied by the induction of epithelial-mesenchymal transition (EMT). LAMC2 knockdown decreased traction force, migration, and invasion accompanied by EMT reduction in vitro, and attenuated metastasis in mice. LAMC2 promoted migration and invasion via EMT that was integrin β1-and ZEB1-dependent. High LAMC2 was significantly correlated with the mesenchymal marker vimentin expression in lung adenocarcinomas, and with higher risk of recurrence or death in patients with lung adenocarcinoma. We suggest that LAMC2 promotes metastasis in lung adenocarcinoma via EMT and may be a potential therapeutic target. Cell Death and Differentiation (2015) 22, 1341-1352; doi:10.1038/cdd.2014.228; published online 16 January 2015Lung cancer is the leading cause of cancer-related death. 1 Non-small-cell lung cancer (NSCLC) accounts for~80-85% of lung cancers. 2 Only 20-30% of NSCLC are radically resectable and the majority of lung cancer patients succumb to the disease. The high mortality of NSCLC is largely attributable to late diagnosis, when metastases are present. 2 The molecular mechanisms governing metastasis of NSCLC remain poorly understood.Metastasis is a complex, multistep process, involving migration and invasion of malignant cells from the primary tumor to blood vessels, intravasation, and survival in the circulation, and ultimately extravasation, colonization, and formation of secondary tumor at distant target organs. 3 Each of these events is classically driven by the acquisition of genetic and/or epigenetic traits in tumor cells and the cooperation of nonneoplastic stromal cells. Increased or decreased expression of several genes in tumors has been found to be correlated with metastasis. 3 However, specific gene alterations that drive NSCLC metastasis remain largely elusive.Laminin γ2 (LAMC2) is a subunit of the heterotrimeric glycoprotein laminin-332 (LAM-332, formerly laminin-5), consisting of the α3, β3, and γ2 chains. Although LAMC2 is an important structural component of the epithelial basement membrane (BM) in various normal tissues, 4 there is an emerging evidence for a pathological role of LAMC2 monomer in cancer. It has been demonstrated that LAMC2 protein expression correlates with clinical outcome of stage I lung adenocarcinoma (ADC) patients. 5,6 In addition, noncontinuous expression pattern of LAMC2 predicts the prognosis of esophageal squamous cell carcinoma (SCC), 7 and secreted LAMC2 in the serum is associated with the aggressiveness of pancreatic cancer. 8 Besides, LAMC2 monom...

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“…4). Type 1 studies have compared the non-metastatic to metastatic primary tumors of different patients to discover genetic markers for metastasis (15,16). However, more specifically, they were designed to study dissemination, as the focused clinical variable is the presence or absence of metastatic spreads at the time of surgical resection.…”

Section: Discussionmentioning

confidence: 99%

“…However, more specifically, they were designed to study dissemination, as the focused clinical variable is the presence or absence of metastatic spreads at the time of surgical resection. By the nature of the study design, the samples of type 1 cannot be obtained from the same patient, and therefore type 1 study models often include many samples to overcome the person-to-person genetic variation (15,16). On the contrary, type 2 studies (longitudinal study models) have compared the 2 chronological samples separated by the colonization event under the identical genetic background of the same patient.…”

Section: Discussionmentioning

confidence: 99%

Differential gene expression during colon-to-lung metastasis

Kim

Choi²,

Cho³

et al. 2011

Oncol Rep

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Abstract. Primary tumors in certain metastatic cases have potential dissemination mechanisms. However, they often lack the potential to colonize distant microenvironments, and consequently the disseminated cancer cells enter into a state of latency which can last for years. In order to investigate the metastatic colonization potential at the gene expression level, we compared such primary tumors with their matching, actively proliferating metastatic tumors. Six pairs of colonto-lung metachronous tumor samples were examined for the expression levels of 84 well-known metastatic genes using the quantitative RT-PCR-based PCR Array technology. The unsupervised hierarchical clustering of all 12 samples together, resulted in the formation of one closely related cluster by the primary tumors, but highly diversified ones by the metastatic tumors. A pair-wise comparison of the matching primarymetastatic tumors showed that different groups of genes were activated in the lung metastases. Therefore we charted specific genes involved in the genetic diversification processes. A number of these genes showed similar differential expression (ΔCt) patterns in all the patients. These were the cancer cell-, the microenvironment-and the stem cell-specific gene groups. In conclusion, the results suggest that the primary colorectal cancer cells are diversified as regards colonization of the lung, which could explain why the effective therapies for primary colorectal cancers are often not appropriate for controling the growth of pulmonary metastases. IntroductionMetastasis can be viewed as two consecutive cellular processes: Dissemination of the cancer cells from the primary tumor to distant sites, and colonization of the disseminated cancer cells of microscopic size into full-blown metastatic malignancies (1,2). When disseminated to a distant microenvironment, most cancer cells can no longer grow in the alien microenvironment, and thus enter into a state of latency which can last for months or years until they discover new growth mechanisms (3-5). Understanding how the micrometastases come out of their latent state to colonize the distant organ is of prime interest, as it could lead us to a therapeutic means of controling the process. However, such studies are generally not practically feasible, as metastasectomies are rarely performed, and even in those rare cases, the invasiveness of the matching primary tumors often decreases during the latent years.However, recent trends of aggressive metastasectomy, particularly of lung metastases of colorectal origin (6,7), could shed a light on this problem. Surgical resection of metastatic tumors is usually performed when, i) recurrence is not detected in the primary site, ii) complete surgical removal of the metastases is feasible, iii) there is no evidence of metastasis in other organs other than the lung, and iv) the patient can tolerate the surgery (6). The tumors removed thereby, are chronologically separated during the latent periods, and genetic differences (5,8) reflect the changes in t...

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Prediction of Recurrence-Free Survival in Postoperative Non–Small Cell Lung Cancer Patients by Using an Integrated Model of Clinical Information and Gene Expression

Cited by 233 publications

References 46 publications

Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer

Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer

LAMC2 enhances the metastatic potential of lung adenocarcinoma

Differential gene expression during colon-to-lung metastasis

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