Unknown,Transcriptomics,Genomics,Proteomics

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Redefining the Relevance of Established Cancer Cell Lines to the Study of Clinical Anti-Cancer Drug Resistance

ABSTRACT: Although in vitro models have been a cornerstone of anti-cancer drug development, their direct applicability to clinical cancer research has actually been uncertain. Using a state-of-the-art Taqman-based qRT-PCR assay, we investigated the multidrug resistance (MDR) transcriptome of six cancer types, in both in vitro and in vivo samples. We studied 380 MDR genes, selected a priori based on an extensive curation of the literature published during the last three decades, in established cancer cell lines and clinical samples, either containing greater than 75% tumor cells or microdissected.

ORGANISM(S): Homo sapiens

SUBMITTER: jean-pierre gillet

PROVIDER: E-GEOD-30034 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Redefining the relevance of established cancer cell lines to the study of mechanisms of clinical anti-cancer drug resistance.

Gillet Jean-Pierre JP Calcagno Anna Maria AM Varma Sudhir S Marino Miguel M Green Lisa J LJ Vora Meena I MI Patel Chirayu C Orina Josiah N JN Eliseeva Tatiana A TA Singal Vineet V Padmanabhan Raji R Davidson Ben B Ganapathi Ram R Sood Anil K AK Rueda Bo R BR Ambudkar Suresh V SV Gottesman Michael M MM

Proceedings of the National Academy of Sciences of the United States of America 20111108 46

Although in vitro models have been a cornerstone of anti-cancer drug development, their direct applicability to clinical cancer research has been uncertain. Using a state-of-the-art Taqman-based quantitative RT-PCR assay, we investigated the multidrug resistance (MDR) transcriptome of six cancer types, in established cancer cell lines (grown in monolayer, 3D scaffold, or in xenograft) and clinical samples, either containing >75% tumor cells or microdissected. The MDR transcriptome was determined ...[more]

PMID: 22068913

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Project description:The presence of tumor cells in effusions within serosal cavities is a clinical manifestation of advanced-stage cancer and is generally associated with poor survival. Identifying molecular targets may help to design efficient treatments to eradicate these aggressive cancer cells and improve patient survival. Using a state-of-the-art Taqman-based qRT-PCR assay, we investigated the multidrug resistance (MDR) transcriptome of 32 unpaired ovarian serous carcinoma effusion samples obtained at diagnosis or at disease recurrence following chemotherapy. MDR genes were selected a priori based on an extensive curation of the literature published during the last three decades. We found three gene signatures with a statistically significant correlation with overall survival (OS), response to treatment (complete response - CR vs. other), and progression free survival (PFS). The median log-rank p-values for the signatures were 0.023, 0.034, and 0.008, respectively. No correlation was found with residual tumor status after cytoreductive surgery, treatment (with or without chemotherapy) and stage defined according to the International Federation of Gynecology and Obstetrics. Further analyses demonstrated that gene expression alone can effectively predict the survival outcome of women with ovarian serous carcinoma (OS: log-rank p=0.0000 and PFS: log-rank p=0.002). Interestingly, the signature for overall survival is the same in patients at first presentation and those who had chemotherapy and relapsed. This pilot study highlights two new gene signatures that may help in optimizing the treatment for ovarian carcinoma patients with effusions. In the study presented here, effusion samples were obtained from 32 patients diagnosed with serous ovarian carcinoma (n=25), primary peritoneal serous carcinoma (n=6) or tubal serous carcinoma (n=1). They were accrued at the Division of Pathology in the Norwegian Radium Hospital from 2000-2006. RNA was used to study the expression profile of 381 multidrug resistant-related genes.

Project description:In the effort to identify novel, relevant prognostic factors for the clinical monitoring of patients affected by squamous cell carcinomas of the oral cavity (SCCOC) we have pursued a molecular screening at the gene and protein level on 166 surgical specimens derived from patients with an accessible clinical history and >2 years follow-up. The screening was focalized on cell surface proteoglycans (PGs) based upon the assumption that altered expression of individual or groups of PGs may predict disease course and therapeutic response, and thereby allow for a clusterization of patients in discrete subsets. The 11 PGs contemplated in the screening and including syndecan-1-4 (SDC1-SDC4), glypican-1-6 (GPC1-GPC6) and NG2, were found to be transcribed at variable levels and with a decreasing frequencies SDC1>SDC4>SDC2>SDC3>GPC4>GPC3>GPC1 >GPC5>CSPG4>GPC6>GPC2. SCCOC cells de novo transcribed GPC2, GPC5 and NG2 and regulated all SDCs, GPC1, -3, -4 and -6, suggesting that an altered surface profile of PG is a characterizing trait of these tumor cells In situ distributional analysis of these PGs on a total of 149 cases revealed many fewer lesions actually translated the molecules which were detected with a frequency range of 14% (SDC2) to 92% (SDC1). Noteworthy was, however, that SDC2 was present in the intra-lesional stroma and in association with neovessels in all the cases, suggesting that this specific PG was a key element of stromal fibroblasts and angiogenic structures. Poor translational efficacy of several of the PGs was accompanied by an apparent retention of the molecules within the cytoplasm of SCCOC cells. This finding suggest that modulated expression of cell surface PGs may be a representative secondary event in SCCOC and that these carcinoma cells do not mount up an effective intracellular machinery for proper shuttling and membrane incorporation of the PGs. A total of 166 surgical specimens of primary SCCOC were collected after informed consent from individuals who underwent surgical removal of the tumor lesions and RNA from 119 surgical specimens were extracted; a pool of RNAs extracted from 5 normal epithelia tissues was adopted as a sample calibrator (HEALTHY sample). cDNA from each samples and from pool of normal epithelial were loaded on TLDA and amplified. HEALTHY sample were amplified 20 times in two replicates (in each TLDA card); each patient sample were amplified 1 time in two replicates and 7 samples of them were loaded two times in a separate TLDA card (for a total of 4 replicates).

Dataset Information

Redefining the Relevance of Established Cancer Cell Lines to the Study of Clinical Anti-Cancer Drug Resistance

Publications

Redefining the relevance of established cancer cell lines to the study of mechanisms of clinical anti-cancer drug resistance.

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