Identification of bronchioalveolar stem cells in normal lung and lung cancer

Injury models have suggested that the lung contains anatomically and functionally distinct epithelial stem cell populations. We have isolated such a regional pulmonary stem cell population, termed bronchioalveolar stem cells (BASCs). Identified at the bronchioalveolar duct junction, BASCs were resistant to bronchiolar and alveolar damage and proliferated during epithelial cell renewal in vivo. BASCs exhibited self-renewal and were multipotent in clonal assays, highlighting their stem cell properties. Furthermore, BASCs expanded in response to oncogenic K-ras in culture and in precursors of lung tumors in vivo. These data support the hypothesis that BASCs are a stem cell population that maintains the bronchiolar Clara cells and alveolar cells of the distal lung and that their transformed counterparts give rise to adenocarcinoma. Although bronchiolar cells and alveolar cells are proposed to be the precursor cells of adenocarcinoma, this work points to BASCs as the putative cells of origin for this subtype of lung cancer.     

Phosphatidylinositol 3-kinase mediates bronchioalveolar stem cell expansion in mouse models of oncogenic K-ras-induced lung cancer

Background

Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related death in Western countries. Developing more effective NSCLC therapeutics will require the elucidation of the genetic and biochemical bases for this disease. Bronchioalveolar stem cells (BASCs) are a putative cancer stem cell population in mouse models of oncogenic K-ras-induced lung adenocarcinoma, an histologic subtype of NSCLC. The signals activated by oncogenic K-ras that mediate BASC expansion have not been fully defined.

Methodology/Principal Findings

We used genetic and pharmacologic approaches to modulate the activity of phosphatidylinositol 3-kinase (PI3K), a key mediator of oncogenic K-ras, in two genetic mouse models of lung adenocarcinoma. Oncogenic K-ras-induced BASC accumulation and tumor growth were blocked by treatment with a small molecule PI3K inhibitor and enhanced by inactivation of phosphatase and tensin homologue deleted from chromosome 10, a negative regulator of PI3K.

Conclusions/Significance

We conclude that PI3K is a critical regulator of BASC expansion, supporting treatment strategies to target PI3K in NSCLC patients.     

MicroRNA expression profile of bronchioalveolar stem cells from mouse lung

Increasing evidence has suggested that bronchioalveolar stem cell (BASC) is the progenitor cells of lung cancer stem cells. However, the mechanisms by which self-renewal of BSACs is controlled and how BASCs turn into cancer stem cells still remains to be unknown. In the present study, we successfully isolated bronchioalveolar stem cells (BASCs) from mouse lung using FACS. These BASCs were characterized by clonal growth, self-renewal and high capacity for differentiation, suggesting that these BASCs are indeed stem cells. We investigated the microRNA (miRNA) expression profile of these BASCs using miRNA array and quantitative RT-PCR. We discovered that BASCs possessed a unique miRNA profile, with altered expression of several microRNAs, such as miR-142-3p, miR-451, miR-106a, miR-142-5p, miR-15b, miR-20a, miR-106b, miR-25, miR-486, in BASCs compared to control cells. Our results suggest that microRNAs might play important roles in maintaining the self-renewal capacity of BASCs, and suggest the intriguing possibility that aberrant expression of microRNAs could involved in turning BASCs into lung cancer stem cells.     

Cellular kinetics and modeling of bronchioalveolar stem cell response during lung regeneration

Organ regeneration in mammals is hypothesized to require a functional pool of stem or progenitor cells, but the role of these cells in lung regeneration is unknown. Whereas postnatal regeneration of alveolar tissue has been attributed to type II alveolar epithelial cells (AECII), we reasoned that bronchioalveolar stem cells (BASCs) have the potential to contribute substantially to this process. To test this hypothesis, unilateral pneumonectomy (PNX) was performed on adult female C57/BL6 mice to stimulate compensatory lung regrowth. The density of BASCs and AECII, and morphometric and physiological measurements, were recorded on days 1, 3, 7, 14, 28, and 45 after surgery. Vital capacity was restored by day 7 after PNX. BASC numbers increased by day 3, peaked to 220% of controls (P<0.05) by day 14, and then returned to baseline after active lung regrowth was complete, whereas AECII cell densities increased to 124% of baseline (N/S). Proliferation studies revealed significant BrdU uptake in BASCs and AECII within the first 7 days after PNX. Quantitative analysis using a systems biology model was used to evaluate the potential contribution of BASCs and AECII. The model demonstrated that BASC proliferation and differentiation contributes between 0 and 25% of compensatory alveolar epithelial (type I and II cell) regrowth, demonstrating that regeneration requires a substantial contribution from AECII. The observed cell kinetic profiles can be reconciled using a dual-compartment (BASC and AECII) proliferation model assuming a linear hierarchy of BASCs, AECII, and AECI cells to achieve lung regrowth.     

Paving the road for lung stem cell biology: bronchioalveolar stem cells and other putative distal lung stem cells

New discoveries in stem cell biology are making the biology of solid tissues increasingly complex. Important seminal studies demonstrating the presence of damage-resistant cell populations together with new isolation and characterization techniques suggest that stem cells exist in the adult lung. More detailed in vivo molecular and cellular characterization of bronchioalveolar stem cells (BASCs), other putative lung stem and progenitor cells, and differentiated cells is needed to determine the lineage relationships in adult lung. Lung diseases such as cystic fibrosis or chronic obstructive pulmonary disease, as well as the most common form of lung cancer in the United States, all involve apparent bronchiolar and alveolar cell defects. It is likely that the delicate balance of stem, progenitor, and differentiated cell functions in the lung is critically affected in patients with these devastating diseases. Thus the discovery of BASCs and other putative lung stem cells will lay the foundation for new inroads to understanding lung biology related to lung disease.     

Differential diagnosis of deforming bronchitis and the peribronchial form of central lung cancer

Bronchofibroscopy was performed in 4736 patients in the Moscow Endoscopic Center (S. P. Botkin Hospital) over the period of September 1984-December 1987. Central lung cancer was diagnosed in 139, of them peribronchial tumor growth was determined in 15. Deforming bronchitis was diagnosed in 283 patients, 23 of them were admitted to hospital with the diagnosis of central lung cancer. Differential diagnosis of peribronchial central lung cancer and deforming bronchitis is based on findings of a combined study including roentgenography, tomography, bronchofibroscopy with biopsy for subsequent cytological and histological investigation.     

Chemotherapy of lung cancer

The potential for substantial improvement in the outcome of patients with carcinoma of the lung seem most likely to develop in the field of chemotherapy. In the past decade, striking advances in the management of small cell carcinoma have yielded response rates and longer survival. While the greatest improvement can be predicted for patients whose disease is limited in extent, combination chemotherapy and combined modality therapy generally are effective in causing tumor regression for the majority of patients. About 20 percent of patients with disease limited to the thorax and lymph nodes will survive two years. In non-small cell tumors, response rates are improved with intensive drug combinations, although the majority of cases are unresponsive to present regimens. Careful staging and evaluation of patients indicates that patients with good performance status and limited extent of disease appear to obtain the most benefit from intensive treatment. The considerable morbidity of some treatments often influences the choice for or against chemotherapy in patients with non-small cell carcinomas. For the future, problems of particular interest will be in investigation of factors-biologic, pharmacokinetic, immunologic-that are related to the failure to cure small cell carcinoma, the most therapeutically responsive pulmonary tumor. Additionally, in the non-small cell tumors, more effective therapies as well as clarification of the basis for relative resistance to cytotoxic agents are areas for intensive investigation.     

Epidemiology of lung cancer

This review article presents lung cancer epidemiology, describing main epidemiologic characteristics including epidemiological situation in cancer incidence, mortality and survival in Europe in comparison with situation in the Czech Republic. Influence of environmental and life style risk factors like smoking, passive smoking, risk factors of work environment, ionizing radiation, air pollution, nutrition and genetic and hormonal factors are discussed.     

Diagnosis of lung cancer

Lung cancer is the most common malignant tumor among male and second among female. The most effective diagnostic tool would be the early detection of the lung cancer. The diagnosis of tumors has to be based on patho-morphological findings. The invasive diagnostic tools can be used if the proved lung process has any therapeutic consequence. Only an experienced team has the chance to examine quickly and effectively the patients.In Hungary there are pulmonological centers where these teams consisting of pneumonologist, radiologists and pathologists are working effectively.     

ErbBs in lung cancer

Lung cancer remains the leading cause of cancer deaths worldwide, and advanced stage disease is largely refractory to conventional chemotherapy. Thus, there is an important need for alternative treatment strategies, and the ErbB proteins have emerged as potentially important therapeutic drug targets in this setting, apparently reflecting a state of “oncogene addiction” in some lung tumors. In this review, we discuss the recent identification of mutations that promote activation of ErbB family proteins in a subset of lung cancers, and the development of selective inhibitors of these proteins that have demonstrated clinical efficacy. We also discuss the problem of drug resistance, which severely limits the clinical utility of such agents, and has prompted intense efforts to better understand molecular mechanisms underlying drug resistance as well as strategies to overcome or prevent such resistance.     

Electrochemical treatment of lung cancer

A pilot study of electrochemical treatment (ECT) as a therapy for 386 patients with nonsmall cell lung cancer was undertaken. There were 103 stage II cases, 89 stage IIIa cases, 122 stage IIIb cases, and 72 stage IV cases. Two ECT methods were used: For peripherally located lung cancer, platinum electrodes were inserted transcutaneously into the tumor under x-ray or CT guidance. For central type lung cancer or for those inoperable during thoracotomy, electrodes were inserted intraoperatively directly into the cancer. Voltage was 6–8 V, current was 40–100 mA, and electric charge was 100 coulombs per cm of tumor diameter. The number of electrodes was determined from the size of cancer mass, because the diameter of effective area around each electrode is approximately 3 cm. The short-term (6 months after ECT) results of the 386 lung cancer cases were: complete response (CR), 25.6% (99/386); partial response (PR), 46.4% (179/386); no change (NC), 15.3% (59/386); and progressive disease (PD), 12.7% (49/386). The total effective rate (CR + PR) was 72% (278/386). The 1, 3, and 5 year overall survival rates were 86.3% (333/386), 58.8% (227/386), and 29.5% (114/386), respectively. The main complication was traumatic pneumothorax, with an incidence rate of 14.8% (57/386). These clinical results show that ECT is simple, safe, effective, and minimally traumatic. ECT provides an alternative method for treating lung cancers that are conventionally inoperable, that are not responsive to chemotherapy or radiotherapy, or that cannot be resected after thoracotomy. Long-term survival rates suggest that ECT warrants further investigation. Bioelectromagnetics 18:8–13, 1997. © 1997 Wiley-Liss, Inc.