Putative tumor-initiating progenitor cells predict poor lung cancer prognosis

Adult lung stem cells, vital to injury repair, associated with poor cancer prognosis, News release, UCLA Newsroom, August 17, 2010. Excerpts:

Adult stem cells that are vital for airway repair in the lung but that persist in areas where pre-cancerous lesions are found are associated with a poor prognosis in patients who develop cancer, even those with early-stage disease, researchers at UCLA's Jonsson Comprehensive Cancer Center have found.

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In this study, Gomperts and her team screened around 900 tumors removed from patients with non-small cell lung cancer at UCLA and the University of Texas' MD Anderson Cancer Center, looking to see whether the adult stem cells could be found in the tumor. In her lab, Gomperts is now studying the pre-cancerous lesions where the adult stem cells persist in an attempt to uncover the cascade of molecular events that may transform these cells into lung cancer stem cells.

The news release is based on this publication: Presence of a Putative Tumor-Initiating Progenitor Cell Population Predicts Poor Prognosis in Smokers with Non–Small Cell Lung Cancer by Aik T Ooi and 19 co-authors, including Brigitte N Gomperts, Cancer Res 2010(Aug 15); 70(16): 6639-48. [PubMed citation][Full text]. Abstract:

Smoking is the most important known risk factor for the development of lung cancer. Tobacco exposure results in chronic inflammation, tissue injury, and repair. A recent hypothesis argues for a stem/progenitor cell involved in airway epithelial repair that may be a tumor-initiating cell in lung cancer and which may be associated with recurrence and metastasis. We used immunostaining, quantitative real-time PCR, Western blots, and lung cancer tissue microarrays to identify subpopulations of airway epithelial stem/progenitor cells under steady-state conditions, normal repair, aberrant repair with premalignant lesions and lung cancer, and their correlation with injury and prognosis. We identified a population of keratin 14 (K14)-expressing progenitor epithelial cells that was involved in repair after injury. Dysregulated repair resulted in the persistence of K14+ cells in the airway epithelium in potentially premalignant lesions. The presence of K14+ progenitor airway epithelial cells in NSCLC predicted a poor prognosis, and this predictive value was strongest in smokers, in which it also correlated with metastasis. This suggests that reparative K14+ progenitor cells may be tumor-initiating cells in this subgroup of smokers with NSCLC.

CSC news update 2010-07-03

For links to recent news items about CSC, visit this [Topsy] page. An example of a news item that has received attention in the past week:

Cancer Stem Cells Are Not 'One Size Fits All,' Lung Cancer Models Show http://bit.ly/bE9F0V & http://bit.ly/amEkFR. Hashtag: #cancerSC. Posted to Twitter on Fri Jul 02 via TweetDeck

Aurothiomalate being studied in a preclinical lung cancer model

Mayo Clinic researchers find lung cancer oncogene holds key to turning off cancer stem cells, News Release, Mayo Clinic, September 8, 2009. First two paragraphs:

Scientists at the Mayo Clinic campus in Florida have found that the lung cancer oncogene PKCiota is necessary for the proliferation of lung cancer stem cells. These stem cells are rare and powerful master cells that manufacture the other cells that make up lung tumors and are resistant to chemotherapy treatment.

Their study, published in the Oct. 1 issue of Cancer Research, also shows that an agent, aurothiomalate, being tested at Mayo Clinic in a phase I clinical trial substantially inhibits growth of these cancer stem cells.

The news release is about this publication: Atypical Protein Kinase C{iota} Is Required for Bronchioalveolar Stem Cell Expansion and Lung Tumorigenesis by Roderick P Regala and 5 co-authors, including Alan P Fields, Cancer Res 2009(Sep 8) [Epub ahead of print][PubMed Citation]. The final paragraph of the full text:

Our present results show that aurothiomalate exhibits potent antiproliferative activity toward the tumor stem cell niche in a relevant preclinical lung cancer model. Future studies will be required to assess whether aurothiomalate has similar antiproliferative effects on human lung cancer stem cells isolated from primary human lung tumors.

Comment: The publication reports results that were obtained using a mouse model. The News Release states that a Phase I clinical trial is under way at the Mayo Clinic, but this trial isn't mentioned in the full text of the publication in Cancer Research. According to MedicineNet.com, aurothiomalate is a "gold-containing chemical (salt) used in treating rheumatoid arthritis".

Malignant Pleural Effusions (MPE) as a model

Researchers Develop Model that May Help Identify Lung Cancer Stem Cells, News Release, UCLA Jonsson Comprehensive Cancer Center, June 16, 2009. First paragraph:

Researchers at UCLA’s Jonsson Comprehensive Cancer Center, on a quest to find lung cancer stem cells, have developed a unique model to allow further investigation into the cells that many believe may be at the root of all lung cancers.

See also: Researchers Use Malignant Pleural Effusion as Model for Lung Cancer, Genetic Engineering & Biotechnology News, June 16, 2009.

Based on: The Malignant Pleural Effusion as a Model to Investigate Intratumoral Heterogeneity in Lung Cancer by Saroj K Basak and 7 co-authors, including Raj K Batra, PLoS ONE 2009(Jun 12); 4(6): e5884 [Entry in FriendFeed]. Abstract:

Malignant Pleural Effusions (MPE) may be useful as a model to study hierarchical progression of cancer and/or intratumoral heterogeneity. To strengthen the rationale for developing the MPE-model for these purposes, we set out to find evidence for the presence of cancer stem cells (CSC) in MPE and demonstrate an ability to sustain intratumoral heterogeneity in MPE-primary cultures. Our studies show that candidate lung CSC-expression signatures (PTEN, OCT4, hTERT, Bmi1, EZH2 and SUZ12) are evident in cell pellets isolated from MPE, and MPE-cytopathology also labels candidate-CSC (CD44, cMET, MDR-1, ALDH) subpopulations. Moreover, in primary cultures that use MPE as the source of both tumor cells and the tumor microenvironment (TME), candidate CSC are maintained over time. This allows us to live-sort candidate CSC-fractions from the MPE-tumor mix on the basis of surface markers (CD44, c-MET, uPAR, MDR-1) or differences in xenobiotic metabolism (ALDH). Thus, MPE-primary cultures provide an avenue to extract candidate CSC populations from individual (isogenic) MPE-tumors. This will allow us to test whether these cells can be discriminated in functional bioassays. Tumor heterogeneity in MPE-primary cultures is evidenced by variable immunolabeling, differences in colony-morphology, and differences in proliferation rates of cell subpopulations. Collectively, these data justify the ongoing development of the MPE-model for the investigation of intratumoral heterogeneity, tumor-TME interactions, and phenotypic validation of candidate lung CSC, in addition to providing direction for the pre-clinical development of rational therapeutics.