Targeting Lung Cancer Stem Cells Research Articles

The analysis of boric acid effect on epithelial-mesenchymal transition of CD133 + CD117 + lung cancer stem cells.

Targeting lung cancer stem cells (LC-SCs) for metastasis may be an effective strategy against lung cancer. This study is the first on epithelial-mesenchymal transition (EMT) properties of boric acid (BA) in LC-SCs. LC-SCs were isolated using the magnetic cell sorting (MACS) method. Tumor-sphere formation and flow cytometry confirmed CSC phenotype. The cytotoxic effect of BA was measured by MTT analysis, and the effect of BA on EMT was examined by migration analysis. The expression levels of ZEB1, SNAIL1, ITGA5, CDH1, ITGB1, VIM, COL1A1, and LAMA5 genes were analyzed by RT-qPCR. E-cadherin, Collagen-1, MMP-3, and Vimentin expressions were analyzed immunohistochemically. Boric acid slightly reduced the migration of cancer cells. Increased expression of transcription factor SNAIL (p < 0.001), but not ZEB1, was observed in LC-SCs. mRNA expression levels of ITGB1 (p < 0.01), ITGA5 (p < 0.001), COL1A1 (p < 0.001), and LAMA5 (p < 0.001) increased; CDH1 and VIM decreased in LC-SCs. Moreover, while E-cadherin (p < 0.001) and Collagen-1 (p < 0.01) immunoreactivities significantly increased, MMP-3 (p < 0.001) and Vimentin (p < 0.01) immunoreactivities decreased in BA-treated LC-SCs. To conclude, the current study provided insights into the efficacy and effects of BA against LC-SCs regarding proliferation, EMT, and cell death for future studies.

Role of Natural compounds to target Lung Cancer Stem Cells

The innovative information about the molecular study has generated a prototype change in the insight of lung cancer, enlightening the more accurate mark for anticancerous drug design. Lung cancer is an imperative origin of tumor death all over the world and it accounts for ~ 1 in 5 of total tumor-related mortalities. Nonsmall cell lung cancer (NSCLC) is one of the deadliest diseases among cancer types. We mainly focused on the role of natural compounds in targeting NSCLC promising favorable results in tumor dissemination. Numerous studies have shown that drug resistance and relapse in tumor lead to the failure of conventional therapy. The utmost crucial reasons for demise in a tumor comprise the therapy letdown and also a disseminating of tumor cells to reserved positions in which the CSC inside the cancer is recognized as a crucial driver. A cancer stem cell is an erratic distinct inhabitant of tumor cells unveiling significant carcinogenic characteristics composed of self-regeneration and discrepancy ability. Moreover, new beneficial methods targeting these cancer stem cells are deliberated to enhance long-term proven outcomes. Herein, we outlined the cancer stem cells in lung cancer, existing CSC markers and favorable molecules targeting the SC signals in lung growth that might profit the growth of innovative NSCLC therapy.

A novel DNA aptamer targeting lung cancer stem cells exerts a therapeutic effect by binding and neutralizing Annexin A2

Cancer remains one of the leading causes of death worldwide. Cancer stem cells (CSCs) are the underlying reason for tumor recurrence, progression, and therapeutic resistance. Aptamers are synthetic single-stranded oligonucleotides that can specifically bind to various molecular targets. Here, we aim to develop an effective aptamer-based biomarker and therapeutic tool that targets CSCs for cancer therapy. We perform whole-cell-based systematic evolution of ligands by exponential enrichment (cell-SELEX) to screen DNA aptamers that specifically bound to lung CSCs, modeled by E-cadherin-silenced A549 cells. We develop a CSC-specific aptamer (AP-9R) specifically recognizing lung CSCs with high affinity and identify Annexin A2, a Ca2+-dependent membrane-binding protein, as its target. Annexin A2 expression was upregulated in lung CSCs and involved in cancer stemness. The expression of Annexin A2 was associated with signatures of stemness and metastasis, as well as poor clinical outcomes, in lung cancer in silico. Moreover, AP-9R decreased Annexin A2 expression and suppressed CSC properties in CSCs in vitro and in vivo. The present findings suggest that Annexin A2 is a CSC marker and regulator, and the CSC-specific aptamer AP-9R has potential theranostic applications for lung cancer.

Understanding Lung Carcinogenesis from a Morphostatic Perspective: Prevention and Therapeutic Potential of Phytochemicals for Targeting Cancer Stem Cells.

Lung cancer is still one of the deadliest cancers, with over two million incidences annually. Prevention is regarded as the most efficient way to reduce both the incidence and death figures. Nevertheless, treatment should still be improved, particularly in addressing therapeutic resistance due to cancer stem cells—the assumed drivers of tumor initiation and progression. Phytochemicals in plant-based diets are thought to contribute substantially to lung cancer prevention and may be efficacious for targeting lung cancer stem cells. In this review, we collect recent literature on lung homeostasis, carcinogenesis, and phytochemicals studied in lung cancers. We provide a comprehensive overview of how normal lung tissue operates and relate it with lung carcinogenesis to redefine better targets for lung cancer stem cells. Nine well-studied phytochemical compounds, namely curcumin, resveratrol, quercetin, epigallocatechin-3-gallate, luteolin, sulforaphane, berberine, genistein, and capsaicin, are discussed in terms of their chemopreventive and anticancer mechanisms in lung cancer and potential use in the clinic. How the use of phytochemicals can be improved by structural manipulations, targeted delivery, concentration adjustments, and combinatorial treatments is also highlighted. We propose that lung carcinomas should be treated differently based on their respective cellular origins. Targeting quiescence-inducing, inflammation-dampening, or reactive oxygen species-balancing pathways appears particularly interesting.

Targeting lung cancer stem cells using combination of Tel and Docetaxel liposomes in 3D cultures and tumor xenografts

Cancer stem cells (CSCs) accounts for recurrence and resistance to chemotherapy in various tumors. Efficacy of chemotherapeutic drugs is limited by tumor stromal barriers, which hinder their penetration into deep tumor sites. We have earlier shown telmisartan (Tel) pretreatment prior to Docetaxel (DTX) administration enhances anti-cancer effects in non-small cell lung cancer (NSCLC). Herein, we demonstrated for the first time the efficacy of Docetaxel liposomes (DTXPL) in combination with Tel in 3D cultures of H460 cells by using polysaccharide-based hydrogels (TheWell Biosciences) and also in xenograft model of DTX resistant H460 derived CD133+ lung tumors. DTXPL and Tel combination showed enhanced cytotoxicity in H460 WT 3D cultures by two folds. In H460 3D cultures, Tel pretreatment showed increased liposomal uptake. DTXPL and Tel combination treated tumors showed reduction in tumor volume (p < .001), increased apoptosis and downregulation of CSC markers (p < .01) in H460 WT and DTX resistant CD133+ xenograft models.

Abstract 3902: Interleukin-6 blockade, a novel cancer stem cell targeted therapy, attenuates lung cancer tissue construction

Abstract Background: Lung cancer stem cells are considered to be responsible for lung cancer progression and metastasis. However, little is known about how they actually promote aggressive behaviors of lung cancer. Methods: We transduced OCT3/4, SOX2, and KLF4 (hereafter, OSK) into a KRAS-mutated (G12S) human lung adenocarcinoma cell line (A549) using retrovirus vectors. Dome-shaped colonies appeared in the OSK transduced A549 cells from 10 to 15 days after transduction. The colonies were picked up and sub-cultured. We named them OSK-A549-Colony cells. We evaluated cancer stem cell properties in the OSK-A549-Colony cells in terms of their chemo resistance, and sphere formation ability. We also assessed organoids constructing ability by co-culture with mesenchymal stem cells (MSCs) and human umbilical vein epithelial cells (HUVECs) on low attachment plates. To clarify the molecular mechanisms that determined the properties of the OSK-A549-Colony cells, we performed microarray analysis. We further analyzed the molecular mechanisms of organoids construction by OSK-A549-Colony cells and searched for a method to destroy them. Results: The induced OSK-A549-colony cells were significantly more resistant to cisplatin than the parental A549 cells. Sphere forming ability was enhanced in the OSK-A549-Colony cells. Co-culture with MSCs and HUVECs showed that only the OSK-A549-Colony cells were able to construct consolidated organoids in vitro that mimicked bona-fide human lung cancer tissues. We named them “lung cancer organoids”. We found that interleukin-6 (IL-6), which was the most differentially expressed gene in the OSK-A549-Colony cells by microarray analysis, facilitated the formation of lung cancer organoids via the conversion of MSCs into alpha-smooth muscle actin (αSMA)-positive cells. Surprisingly, the combination of anti-IL-6 antibody and cisplatin could destroy the lung cancer organoids, while cisplatin alone could not. Conclusion: By transducing defined factors, A549 cells acquired lung cancer stem cell like properties. Analysis of chemosensitivity using the lung cancer organoids showed that the combination of IL-6 blockade and cisplatin could be a novel therapy targeting lung cancer stem cells. Citation Format: Hiroyuki Ogawa, Michiyo Koyanagi-Aoi, Yoshimasa Maniwa, Takashi Aoi. Interleukin-6 blockade, a novel cancer stem cell targeted therapy, attenuates lung cancer tissue construction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3902. doi:10.1158/1538-7445.AM2017-3902

Curcumin Targets Circulating Cancer Stem Cells by Inhibiting Self-Renewal Efficacy in Non-Small Cell Lung Carcinoma.

The ultimate goal of the study was to find a role of curcumin in targeting lung cancer stem cells by reducing their self-renewal efficiency causing DNA damage. Circulating lung cancer stem cells were isolated by sphere formation assay and further analysed by flow-cytometry and qRT-PCR for the presence of stem cell and stem cell transcription markers. The IC50 values of gemcitabine and curcumin were analysed by MTT assay, while curcumin induced DNA damage was scrutinized by single cell gel electrophoresis assay. Our results demonstrated that curcumin significantly affect the self-renewal ability of circulating lung cancer stem cells. The no. of spheres formed in the presence of curcumin was shown to be significantly decreased. Additionally, our results depicted that 4.52±0.72 % and 95.47±0.72 % (p &lt; 0.0001) of DNA material was found to be present in head and tail, respectively, suggesting curcumin's functional potential to cause DNA damage. Thus, we can conclude that curcumin can be used to target lung cancer stem cells which is responsible for the disease progression and metastasis by causing DNA damage or inhibiting their DNA repair mechanisms.

Targeting Lung Cancer Stem Cells: Research and Clinical Impacts.

Lung cancer is the most common cancer worldwide, accounting for 1.8 million new cases and 1.6 million deaths in 2012. Non-small cell lung cancer (NSCLC), which is one of two types of lung cancer, accounts for 85–90% of all lung cancers. Despite advances in therapy, lung cancer still remains a leading cause of death. Cancer relapse and dissemination after treatment indicates the existence of a niche of cancer cells that are not fully eradicated by current therapies. These chemoresistant populations of cancer cells are called cancer stem cells (CSCs) because they possess the self-renewal and differentiation capabilities similar to those of normal stem cells. Targeting the niche of CSCs in combination with chemotherapy might provide a promising strategy to eradicate these cells. Thus, understanding the characteristics of CSCs has become a focus of studies of NSCLC therapies.

Targeting Lung Cancer Stem Cells with Antipsychological Drug Thioridazine

Lung cancer stem cells are a subpopulation of cells critical for lung cancer progression, metastasis, and drug resistance. Thioridazine, a classical neurological drug, has been reported with anticancer ability. However, whether thioridazine could inhibit lung cancer stem cells has never been studied. In our current work, we used different dosage of thioridazine to test its effect on lung cancer stem cells sphere formation. The response of lung cancer stem cells to chemotherapy drug with thioridazine treatment was measured. The cell cycle distribution of lung cancer stem cells after thioridazine treatment was detected. The in vivo inhibitory effect of thioridazine was also measured. We found that thioridazine could dramatically inhibit sphere formation of lung cancer stem cells. It sensitized the LCSCs to chemotherapeutic drugs 5-FU and cisplatin. Thioridazine altered the cell cycle distribution of LCSCs and decreased the proportion of G0 phase cells in lung cancer stem cells. Thioridazine inhibited lung cancer stem cells initiated tumors growth in vivo. This study showed that thioridazine could inhibit lung cancer stem cells in vitro and in vivo. It provides a potential drug for lung cancer therapy through targeting lung cancer stem cells.

Abstract 4373: Targeting lung cancer stem cells with inhibition of multiple drug resistance by demethoxylcurcumin-carrying chitosan-antibody core-shell nanoparticles

Abstract Lung adenocarcinoma (LAC) has been clinically realized to be one of the most deadly malignant tumors with relatively low in 5-year survival rate. High recurrence rates and drug-resistance potential have been reported in LAC even after completion of combined therapy. Herein we demonstrate that cisplatin treatment selecting for resistance with high self-renewal and invasive capabilities in cisplatin-resistant LAC cell (CisR-LAC). For overcoming the multi-drug resistance (MDR) in CisR-LAC, we designed a multifunctional nanocarrier with enhanced targeting ability and inhibition of MDR inhibition in CisR-LAC. The platform provide a high anti-MDR efficacy via a facile synthesis scheme using an amphiphilic chitosan to encapsulate a demethoxylcurcumin (DMC), as a core phase, following surface modification of an anti-EGFR layer, forming a CHC-DMC/anti-EGFR core-shell nanostructure. Experimental outcomes revealed an enhanced therapeutic efficacy of the DMC, forming DMC nano-precipitates in lysosome and endosome, as a result of efficient cellular endocytosis of the core-shell nanoparticles, by a synergistic action of both MDR inhibition and efficacious cell killing. Animal study showed a significant therapeutic efficacy against CisR-LAC-xenograft lung tumor using the core-shell nanocarriers, by a reduction of as high as 5-folded tumor volume compared with control groups. This result indicated the multi-therapeutic efficacy of the multifunctional CHC-DMC/anti-EGFR core-shell nanoparticle, providing a potential capability in anti-MDR LAC for better clinical translation. Note: This abstract was not presented at the meeting. Citation Format: Shih-Hwa Chiou. Targeting lung cancer stem cells with inhibition of multiple drug resistance by demethoxylcurcumin-carrying chitosan-antibody core-shell nanoparticles. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4373. doi:10.1158/1538-7445.AM2015-4373

Abstract 4230: Targeting lung cancer stem cells through fatty acid metabolism

Abstract Distinctive features of CSC are capacity of self renewal, increased resistance to chemotherapy and the ability to form three dimensional non adherent spheroids in appropriate conditions. We have recently demonstrated that cell cultures derived from malignant pleural effusion (MPE’s) of patients with adenocarcinoma of the lung efficiently form spheroids in non-adherent conditions supplemented with growth factors. By expression profiling, we identified 18 genes whose expression is significantly upregulated in lung tumor spheroids versus adherent cultures. Among the upregulated genes we found five genes involved in lipid metabolism. SCD1, the enzyme involved in the conversion of saturated into monounsaturated fatty acids, was one of those strongly upregulated. We demonstrated that SCD1 inhibition leads to lung cancer spheroid collapse and to the selective apoptosis of ALDH+ cells, a marker enriched in cells with stem like properties. In line with these results we demonstrated by cell sorting that ALDH positive cells were more sensitive to SCD1 inhibition than ALDH negative cells and that treatment with an SCD1 inhibitor strongly enhanced sensitivity of spheroids cells to Cisplatin. Furthermore, we observed that SCD1 inhibited spheroids were strongly impaired in their in vivo tumorigenicity. Using public datasets from lung cancer we conducted a bioinformatics analysis demonstrating that the survival rate of patients expressing SCD1-high levels was significantly lower than that of the patients expressing low level in lung adenocarcinoma. Moreover, we found that the correlation of SCD1 and stemness markers (nanog, CD44, CD24) selects the patients with bad prognosis. These results overall, indicate that SCD1 could be considered a prognostic markers for lung adenocarcinoma and a potential target for therapeutic intervention. Our studies are currently directed to dissect the mechanism pathways leading to SCD1 upregulation in lung cancer stem cells. Citation Format: Alessia Noto, Maria Elena Pisanu, Claudia De Vitis, Debora Malpicci, Luigi Fattore, Nadia Lobello, Barbara Bonacci, Gennaro Ciliberto, Rita Mancini. Targeting lung cancer stem cells through fatty acid metabolism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4230. doi:10.1158/1538-7445.AM2015-4230

A Preclinical Evaluation of Antimycin A as a Potential Antilung Cancer Stem Cell Agent

Drug resistance and tumor recurrence are major obstacles in treating lung cancer patients. Accumulating evidence considers lung cancer stem cells (CSCs) as the major contributor to these clinical challenges. Agents that can target lung CSCs could potentially provide a more effective treatment than traditional chemotherapy. Here, we utilized the side-population (SP) method to isolate lung CSCs from A549 and PC-9 cell lines. Subsequently, a high throughput platform, connectivity maps (CMAPs), was used to identify potential anti-CSC agents. An antibiotic, antimycin A (AMA), was identified as a top candidate. SP A549 cells exhibited an elevated stemness profile, including Nanog, β-catenin, Sox2, and CD133, and increased self-renewal ability. AMA treatment was found to suppress β-catenin signaling components and tumor sphere formation. Furthermore, AMA treatment decreased the proliferation of gefitinib-resistant PC-9/GR cells and percentage of SP population. AMA demonstrated synergistic suppression of PC-9/GR cell viability when combined with gefitinib. Finally, AMA treatment suppressed tumorigenesis in mice inoculated with A549 SP cells. Collectively, we have identified AMA using CMAP as a novel antilung CSC agent, which acts to downregulate β-catenin signaling. The combination of AMA and targeted therapeutic agents could be considered for overcoming drug resistance and relapse in lung cancer patients.

Abstract LB-370: Genetically engineered oncolytic Edmonston strain of measles strain harboring the wild-type N, P, L genes (MV-NPL) effectively target lung cancer stem cells

Abstract Increasing evidence suggests that only a small percentage of cancer cells in solid tumors have tumorigenic potential. These highly tumorigenic cells share with normal stem cells the ability to proliferate and give rise to diversified tumor cell types including those with the capacity for self-renewal. These cells are termed cancer stem cells (CSCs) and are believed to contribute to CSCs resistance to conventional therapies. Therefore, specific targeting of CSCs is an attractive and novel therapeutic approach. Measles virus Edmonston strain (MV-Edm) is thought to possess remarkable oncolytic activity that selectively destroys human tumor cells. Recently, we succeeded and reported the development of novel oncolytic measles virus (MV) by genetic engineering of MV-Edmonston strain (MV-Edm), that have demonstrated its remarkable oncolytic activity against wide ranges of human tumor cells, with the N, P, and L genes of wild-type MV (MV-NPL). The oncolytic activities of the MV-NPL on human renal cell carcinoma were superior to those of MV-Edm both in vitro and in vivo studies even in the presence of IFN[[Unsupported Character - &amp;#8208;]]α[[Unsupported Character - &amp;#61472;]](Xing, M. et. al. Mol Ther 2010). Here, we demonstrated that lung CSCs, side population fraction of human lung cancer cells of A549 (A549-SP), expressed high level of CD46 required for MV-NPL infection and MV-NPL had a superior oncolytic capacity against both A549-SP and A549-NSP (non SP) cells in a time and dose-dependent manner without damaging normal lung cells. Our results of pan-caspase inhibiton assays showed the partial contribution of caspases-dependent apoptosis in the oncolysis of A549-SP cells by MV-NPL, even though the expression levels of anti-apoptotic protein of both XIAP and Mcl-1 were higher in A549-SP cells than A549-NSP cells. Additionally, we demonstrated that an addition of either PI3K inhibitor or MEK inhibitor further enhanced the oncolytic effects of MV-NPL. Furthermore, our in vivo studies using nude mice bearing A549 xenografts revealed that serial intratumoral MV-NPL administrations exhibited significant antitumor effects without severe side effects. Collectively, these data suggested that genetically engineered MV-NPL could be a promising oncolytic agent to effectively eradicate lung CSCs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-370. doi:1538-7445.AM2012-LB-370

Matrix Metalloproteinase-10 Promotes Kras-Mediated Bronchio-Alveolar Stem Cell Expansion and Lung Cancer Formation

Matrix metalloproteinase 10 (MMP-10; stromelysin 2) is a member of a large family of structurally related matrix metalloproteinases, many of which have been implicated in tumor progression, invasion and metastasis. We recently identified Mmp10 as a gene that is highly induced in tumor-initiating lung bronchioalveolar stem cells (BASCs) upon activation of oncogenic Kras in a mouse model of lung adenocarcinoma. However, the potential role of Mmp10 in lung tumorigenesis has not been addressed. Here, we demonstrate that Mmp10 is overexpressed in lung tumors induced by either the smoke carcinogen urethane or oncogenic Kras. In addition, we report a significant reduction in lung tumor number and size after urethane exposure or genetic activation of oncogenic Kras in Mmp10 null (Mmp10−/−) mice. This inhibitory effect is reflected in a defect in the ability of Mmp10-deficient BASCs to expand and undergo transformation in response to urethane or oncogenic Kras in vivo and in vitro, demonstrating a role for Mmp10 in the tumor-initiating activity of Kras-transformed lung stem cells. To determine the potential relevance of MMP10 in human cancer we analyzed Mmp10 expression in publicly-available gene expression profiles of human cancers. Our analysis reveals that MMP10 is highly overexpressed in human lung tumors. Gene set enhancement analysis (GSEA) demonstrates that elevated MMP10 expression correlates with both cancer stem cell and tumor metastasis genomic signatures in human lung cancer. Finally, Mmp10 is elevated in many human tumor types suggesting a widespread role for Mmp10 in human malignancy. We conclude that Mmp10 plays an important role in lung tumor initiation via maintenance of a highly tumorigenic, cancer-initiating, stem-like cell population, and that Mmp10 expression is associated with stem-like, highly metastatic genotypes in human lung cancers. These results indicate that Mmp10 may represent a novel therapeutic approach to target lung cancer stem cells.

Lung cancer stem cells

Recently,studies have demonstrated that several signaling pathways including Wnt,Notch,and Hedgehog which are involved in the regulation of the stem cells are abnormally activated in lung cancer.They are closely associated with some properties of the lung cancer stem cells,such as high tumorigenic,high metastasis,drug resistance and so on.In addition,several studies have shown that the population of the lung cancer stem cells,which are resistant to radiotherapy and chemotherapy significantly,highly express drug resistance proteins.Therefore,how to target lung cancer stem cells and ultimately cure the disease is becoming a hotspot in the cancer targeted therapy. Key words: Lung neoplasms ; Neoplastic stem cells ;

Abstract 502: Development of lung cancer cell lines exhibiting cancer stem cell properties through application of stem-cell culturing techniques

Abstract Introduction: Lung cancer is the most common cause of cancer death worldwide: with greater than 160,000 deaths reported in the US in 2008 and a dismal 15% 5-year survival rate, there is a clear need for improved therapeutic approaches. Considering the increasing evidence for the role of cancer stem cells (CSC) in driving tumor initiation and metastases, development of model systems to isolate and characterize such populations in lung cancer would provide important tools to drive discovery of novel therapeutic modalities. We recently reported application of selective culture conditions to generate novel cell lines from colon cancer that exhibit CSC properties (1). Here we apply a similar approach to lung cancer. Methodology: Freshly resected NSLC tissue was obtained, processed and cultured using serum-free defined culture media previously developed for fetal lung stem cells (2). Expanded cell lines were characterized for their tumor initiating properties in NSG mice upon implantation under the sub-renal capsule. Cell populations generated from lung cancer under serum-containing conditions served as controls. Tumors were analyzed by H&amp;E and immunostaining for specific markers. Gene expression profiles were determined by U133 Affymetrix arraying, and the cell surface protein profile examined by flow cytometry using a bank of approximately ∼200 cell surface reactive mAbs. Results: Lung cancer cell lines, were successfully cultured from independent lung tumor specimens and remained genetically stable upon prolonged passaging in vitro. One such line, LUCA22, was derived from an adenosquamous carcinoma specimen and harbors a KRAS mutation. This line formed tumors in mice within 10 weeks upon implantation of as few as 500 cells; these tumors recapitulated the morphology of the patient's original tumor, with mixed features that included differentiation into both adeno- and squamous-type carcinoma. Within 16 weeks, spontaneous metastases were observed to the lung, liver and pancreas. Gene array analyses of LUCA22 cells compared to control populations revealed up-regulation of genes associated with the Wnt and TGF-beta pathways, while flow cytometry identified over-expression of several CSC-associated cell surface proteins, including CD44. Conclusion: Novel NSCL cell lines have been derived from primary tumor specimens by employing culture conditions previously established for tissue stem cells. These lines display key features ascribed to CSC including the capacity to recapitulate the original tumor morphology from where they were derived and the ability to spontaneously metastasize. Gene array analysis and mAbs library panning of the cell lines are being applied to identify lead opportunities for targeting lung cancer stem cells.

The molecular and cellular biology of lung cancer: identifying novel therapeutic strategies

Lung cancer is the commonest fatal malignancy in the developed world. Survival rates for lung cancer have not changed significantly over the past 30 years. Sources of data This report is a systematic review of the literature on our current understanding of lung cancer biology. Searches were carried out using PUBMED. 1990-2010. A concerted effort to reduce cigarette smoking and nicotine addiction is required. A better understanding of the biology of lung cancer will lead to the identification of earlier diagnostic markers and improved therapy. How chronic inflammatory disorders such as COPD and lung fibrosis contribute to lung cancer development is incompletely understood. Developing novel biological agents to target lung cancer. New microarray-based technologies provide new methods for predicting prognosis and response to treatment. Developing strategies to target lung cancer stem cells may provide a novel approach for treating drug resistant disease.