Purpose: Primary tumor xenografts (PTXG) established directly from patients' primary tumors in immunosuppressed animals might represent the spectrum of histologic complexity of lung cancers better than xenografts derived from established cell lines. These models are important in the study of aberrant biological pathways in cancers and as preclinical models for testing new therapeutic agents. However, not all primary tumors engraft when implanted into immunosuppressed mice. We have investigated factors that may influence the ability of primary non-small cell lung cancer (NSCLC) to form xenografts and their association with clinical outcome.Experimental Design: Tumor fragments from patients undergoing curative surgery were implanted into NOD-SCID (nonobese diabetic-severely combined immunodeficient) mice within 24 hours of surgery. Patient characteristics for tumors that engrafted (XG) and did not engraft (no-XG) were compared. Patient tumor DNA was profiled for the presence of 238 known mutations in 19 cancer-associated genes by using the MassARRAY platform.Results: Xenografts were established and passaged successfully from 63 of 157 (40%) implanted NSCLCs. Tumor factors associated with engraftment included squamous histology, poor differentiation, and larger tumor size. Significantly fewer EGFR (epidermal growth factor receptor)-mutated tumors engrafted (P ¼ 0.03); conversely, more K-RAS-mutated tumors engrafted (P ¼ 0.05). In multivariate analysis including age, sex, stage, and mutation, patients with XG tumors had significantly shorter diseasefree survival compared with no-XG patients (hazard ratio : 7.0, 95% CI: 3.1-15.81; P < 0.000003).Conclusion: PTXGs closely mirror the histology and molecular profiles of primary tumors and therefore may serve as important preclinical models. Tumors that engraft are biologically more aggressive and may be more representative of cancers with a higher propensity to relapse after surgery. Clin Cancer Res; 17(1); 134-41. Ó2010 AACR.

Among stage I lung adenocarcinoma patients, spread through air spaces was found frequently in the invasive cases and was closely related to poor prognosis and recurrence.

No abstract

Aberrant methylation of promoter CpG islands is known to be a major inactivation mechanism of tumor suppressor and tumor-related genes. To determine the clinicopathological significance of gene promoter methylation in non-small cell lung cancer (NSCLC), we examined the promoter methylation status of the APC, DAPkinase, E-cadherin, GSTP1, hMLH1, p16, RASSF1A and RUNX3 genes in 75 NSCLCs and corresponding non-neoplastic lung tissues by methylation-specific PCR (MSP). The frequencies of methylation in NSCLCs and corresponding non-neoplastic lung tissues were: 37% (28 of 75) and 48% (36 of 75) for APC, 28% (21 of 75) and 13% (10 of 75) for DAP-kinase, 29% (22 of 75) and 15% (11 of 75) for E-cadherin, 1% (1 of 75) and 0% (0 of 75) for GSTP1, 7% (5 of 75) and 0% (0 of 75) for hMLH1, 31% (23 of 75) and 0% (0 of 75) for p16, 43% (32 of 75) and 4% (3 of 75) for RASSF1A, and 20% (15 of 75) and 3% (2 of 75) for RUNX3, respectively. Methylation of p16 was more frequent in squamous cell carcinomas than in adenocarcinomas (P < < < <0.05), and was associated with tobacco smoking (P < < < <0.05). On the contrary, methylation of APC and RUNX3 was more frequent in adenocarcinomas than in squamous cell carcinomas (P < < < <0.05). Thus, a different set of genes is thought to undergo promoter methylation, which leads to the development of different histologies. In addition, methylation of p16, RASSF1A and RUNX3 was mostly cancer-specific (P < < < <0.05), and may be utilized as a molecular diagnostic marker of NSCLCs. (Cancer Sci 2003; 94: 589-592) ung cancer is the leading cause of cancer deaths in the world, with over one million cases diagnosed every year. 1)Lung cancers are divided into two major histological types, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), the latter consisting of adenocarcinoma (AdC), squamous cell carcinoma (SCC) and large cell carcinoma. There is a growing body of biological and epidemiological data suggesting that AdC and SCC are distinct etiological entities.2, 3) There are no squamous cells in the normal bronchus, and SCCs are believed to arise from metaplastic cells present in the bronchi of smokers. By contrast, most AdCs may express features of Clara cells or type II pneumocytes. It is well known that the female/male occurrence ratio of AdC is significantly higher than that of SCC. SCC is more common in the central region, but AdC is more common in the peripheral region. Genetically, mutations in p53 and p16 are more common in SCC than AdC, 4,5) although K-ras mutations are more frequent in AdC. 6)Allelic imbalance is more frequent in SCC than AdC. 7, 8) Aberrant methylation of normally unmethylated CpG-rich areas (or islands) in or near the promoter region has been associated with transcriptional inactivation of tumor suppressor and tumor-related genes in human cancers, including NSCLC.9-12) Therefore, it is possible that methylation of different genes may contribute to the development of different histologies. In fact, we have recently determined that p16 methylation is mor...

: The new International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society ADC classification and invasive tumor size are very useful predictors of recurrence of stage I ADCs in Japanese patients.

No abstract

PDX models closely recapitulate primary tumor biology and clinical outcome. They may serve as important laboratory models to investigate mechanisms of resistance to targeted therapies, and for preclinical testing of novel treatment strategies.

Availability of lung cancer models that closely mimic human tumors remains a significant gap in cancer research, as tumor cell lines and mouse models may not recapitulate the spectrum of lung cancer heterogeneity seen in patients. We aimed to establish a patient‐derived tumor xenograft (PDX) resource from surgically resected non‐small cell lung cancer (NSCLC). Fresh tumor tissue from surgical resection was implanted and grown in the subcutaneous pocket of non‐obese severe combined immune deficient (NOD SCID) gamma mice. Subsequent passages were in NOD SCID mice. A subset of matched patient and PDX tumors and non‐neoplastic lung tissues were profiled by whole exome sequencing, single nucleotide polymorphism (SNP) and methylation arrays, and phosphotyrosine (pY)‐proteome by mass spectrometry. The data were compared to published NSCLC datasets of NSCLC primary and cell lines. 127 stable PDXs were established from 441 lung carcinomas representing all major histological subtypes: 52 adenocarcinomas, 62 squamous cell carcinomas, one adeno‐squamous carcinoma, five sarcomatoid carcinomas, five large cell neuroendocrine carcinomas, and two small cell lung cancers. Somatic mutations, gene copy number and expression profiles, and pY‐proteome landscape of 36 PDXs showed greater similarity with patient tumors than with established cell lines. Novel somatic mutations on cancer associated genes were identified but only in PDXs, likely due to selective clonal growth in the PDXs that allows detection of these low allelic frequency mutations. The results provide the strongest evidence yet that PDXs established from lung cancers closely mimic the characteristics of patient primary tumors.