The Daily Sign-Out

SNAI1 functional variant associated with decreased risk for lung cancer

This is an abstract from the January 15, 2014 issue of American Journal of Respiratory and Critical Care Medicino that I just re-discovered this week and relates to one of my ongoing (and unrequited) obsession with epithelial-mesenchymal transition in lung cancer.

It appears that there are five major EMT regulatory genes (SNAI1, SLUG, ZEB1, ZEB2, and TWIST1) involved in EMT.  But--the relative contribution and importance of each of these genes in the development and progression of non-small cell lung cancer is not clear.

 This article adds another layer of complexity and I post it (rather belatedly) now because I find in it such an intriguing finding that a variant protein could have functional consequences that are observable as a clinical outcome with regard to COPD and NSCLC.  Moreover, this variant was discovered to attenuate Snai1’s ability to specifically up-regulate mesenchymal biomarkers (i.e., fibronectin and vimentin) expression, and to promote EMT-like changes, including morphologic changes, cell migration, and invasion.

Major Driver Mutations in Adenosquamous Lung Carcinomas

The June 2014 issue of Journal of Thoracic Oncology (abstract) features a thorough study of major known driver mutations (EGFR, KRAS, ERBB2, BRAF, PIK3CA, AKT1, RET, and ALK) in a series of 76 patients from Fudan University Shanghai Cancer Center with resected adenosquamous lung carcinoma (AdSqLC) by Wang et al. and compared this group with a group of 646 patients with resected adenocarcinoma (ADC) during the same study period.  This is a nifty paper that will serve well as a useful contemporary reference when you next encounter a patient with adenosquamous lung carcinoma.

From their "Table 1" data, it is of note that they found significantly higher smokers in AdSqLC versus ADC.

Known mutant kinases were demonstrated in 57% (43/76) patients.  EGFR mutations were the most common found (32%, 24/76) but were significantly lower compared to the ADC "control" group.  EGFR mutation was significantly higher in never smokers compared to smokers as expected, but it is notable that the frequency of EGFR mutation was higher in glandular dominant AdSqLC than squamous dominant AdSqLC.  Other gene mutations were similar to those found in ADC.  While the frequency of driver mutations was similar between "classical" AdSqLC and poorly-differentiated ADC, the frequency of RET and ALK fusion genes was higher in solid growth glandular component-predominant AdSqLC versus classical AdSqLC.

Microdissection of 13 tumors showed the same mutation in both glandular and squamous components in 9 tumors but 4 of 13 cases showed mutations (KRAS-2, HER2, EGFR) only in the glandular component.

Survival data including 58 AdSqLC and 246 ADC patients showed no significant difference in relapse-free survival between classical AdSqLC, poorly-differentiated ADC, and solid-predominant AdSqLC.  Both classical- and solid-types AdSqLC showed worse overall survival compared to well- and moderately-differentiated ADC.

 

ETS2 mediates tumor suppressor function and MET inhibition in lung adenocarcinoma

There was a very intriguing paper published online by Clinical Cancer Research on May 9 last week that should be of interest for those involved in lung cancer research.  The authors are Mohamed Kabbout, Melinda Garcia, Junya Fujimoto, et al. from M.D. Ancerson Cancer Center in Houston and the title of the article is "ETS2 mediated tumor suppressive function and MET oncogene inhibition in
human non-small cell lung cancer." 

In brief, the authors find that there is significant downregulation of the ETS2 transcription factor in lung adenocarcinomas compared to normal lung tissues.  ETS2 expression is linked to various canonical cancer-associated pathways in lung cancer cells, in particular the HGF pathway.  Moreover, knockdown of ETS2 is associated with up-regulation of the ZEB1, SNAI2, RAB3B, SERPINB5 and SPDEF genes
with concomitant with elevated cell migration and invasion.  Last, low ETS2 protein is predictive of shorter time-to-recurrence in NSCLC and lung adenocarcinoma.  These data suggest that ETS2 functions as a tumor-suppressor in lung cancer cells by, at least in part, regulation of the migration- and invasion-promoting transcriptome.

More details. . .

Gene expression profiling showed significant decreased expression of ETS2 transcription factor transcripts in lung adenocarcinoma (ADC) compared to normal controls and quantitative RT-PCR confirmed decreased ETS2 expression.  Subset analysis should significantly decreased ETS2 expression in those ADCs from smokers compared to those from never-smokers.

They analyzed ETS2 expression by IHC in a microarray set of 201 NSCLC (135 ADC, 66 squamous cell carcinoma-SQC) tumors.  Low ETS2 expression was associated with shorter time-to-recurrence in stage I and all stages of patients.  Multivariate Cox proportional hazards analysis showed that, after adjusting for stage, low ETS2 expression was an independent predictor of shorter time-to-recurrence in NSCLC and ADC.

H441 human lung cancer cell lines transfected with small interfering RNA (siRNA) specific to ETS2 showed significantly reduced ETS2 transcript compared to controls.  ETS2 knockdown significantly increased cell growth, migration, and invasion.  Conversely, ETS2 overexpression in H1299 lung cancer cells showed significantly decreased cell migration and invasion.  Of interest, the magnitude of these changes following knockdown or overexpression of ETS2 was greater in measures of migration and invasion compared to cell growth--suggesting a tumor suppressor function for ETS2 at least in vitro.

Gene expression profiling of H441 lung cancer cell lines transfected with scrambled siRNA (control) versus ETS2-specific siRNA showed significant differential expression in 1,816 transcripts.  Functional analysis by Ingenuity Pathways Analysis (IPA) showed ETS2 knockdown modulated key oncogenic pathways, including HGF, integrin, tissue factor, semaphorin, and MAPK signaling.  Notably, HGF was the top modulated canonical pathway identified following knowdown, and further, an HGF-mediated gene-interaction network was among the among the top significant gene networks following topological arrangement of the genes found to be differentially expressed by IPA.

Western blot analysis and ELISA both showed increased phosphorylation MET following ETS2 knockdown.  Importantly, co-transfection of H441 lung cancer cells with MET-specific siRNA abrogated cell migration, invasion, and, to a lesser effect, cell growth mediated by knockdown of ETS2 expression alone.  Furthermore, co-transfection of cells with MET-specific siRNA significantly attenuated the induction of SNAI2, RAB3B, SPDEF and SERPINB5 mediated by knockdown of ETS2 alone as well as reduced expression of ZEB1. These data demonstrate that ETS2 suppresses key features of the lung cell malignant phenotype, at least in part, through inhibition of the MET oncogene. 

The authors also find that ETS2 suppresses EGF-mediated signaling in lung cancer cells.  HGF treatment increased ETS2 protein expression and phosphorylation of MET and ERK1/2 MAPK in H441 cells.  Conversely, expression of ETS2, phospho-MET, and phospho-ERK1/2 was attenuated by co-treatment of H441 cells with the MET TKI PHA-665752.  HGF treatment also significantly increased the expression of SNAI1, RAB3B, SPDEF, ZEB1, and SERPINB5 genes.  Moreover, the expression of these genes was significantly higher in HGF-treated cells transfected with ETS2-specific siRNA compared to similarly treated control cells.  Conversely, overexpression of ETS2 in H1299 cells decreased HGF-induced phosphorylated MET levels and decreased HGF-induced cell migration in the wound healing assay. 

Finally, NSCLC (p=0.01) or ADC (p=0.02) patients with relatively low ETS2 protein expression and higher phospho-MET membrane immunoreactivity showed shortest tiime-to-recurrence compared to other patient groups, specifically those with higher ETS2 and higher phospho-MET
expression.

Epithelial-Mesenchymal Transition and Lung Cancer: Mechanism for Resistance to EGFR-TKIs?

Despite all of the encouraging clinical results with molecularly targeted therapies against non-small cell lung cancer, there are still important and significant questions that continue to vex.  The discovery of activating mutations in EGFR radically changed the treatment options for these patients, and, indeed, treatment of advanced stage patients with EGFR-mutated tumors with erlotinib (in the US) is now front-line therapy.  However, even patients who initially show dramatic responses invariably relapse due to the development of drug resistance.  Although such resistance can be explained in about 50% of these patients, what are the mechanisms for the other 50%?  Conversely, why do some, albeit rare, patients who are wild-type for EGFR respond to EGFR-TKIs?  Also, why don't conventional chemotherapy and molecularly targeted therapy produce a synergistic effect?  In fact, patients treated with combined therapy seem to actually do worse than if they get just one or the other--why?

Numerous research groups are trying to identify more effective biomarkers to identify predictive markers for response or resistance to EGFR-TKIs in order to optimize therapy for individual patients.  Our group at Rush University Medical Center has been focused on the role of epithelial-mesenchymal transition as a prognostic marker for early-stage NSCLC but also as a predictive marker for response to EGFR-TKIs.  So I read with great interest the article by Byers et al. recently published online in Clinical Cancer Research on December 20, 2012 (abstract here).

Some important notes:

 

• The EMT first principal component correlated better with E-cadherin protein level than did even the best CDH1 mRNA probe set.
• Mesenchymal cell lines were highly resistant to erlotinib as compared to epithelial cell lines, which agrees with previous work.  It is interesting, however, that while cell lines with EGFR-activating mutations were the most sensitive to erlotinib, in a subset of 40 cell lines WT for both EGFR and KRAS, the correlation between EMT signature and erlotinib resistance was still observed with significantly greater resistance in mesenchymal-like cell lines.  An important corollary is that the EMT signature was a better predictor of erlotinib response than mRNA probe sets for either CDH1 (E-cadherin) or VIM genes individually--a finding that agrees with the work we've done in our lab.
• EMT does not appear to be a general marker of resistance.  Indeed, mesenchymal cells were not more resistant to other targeted agents, such as sorafenib or to commonly used cytotoxic chemotherapies, including pemetrexed, docetaxel, paclitaxel, and platinum-doublets. Instead, a trend toward greater relative sensitivity was seen in mesenchymal cells as compared with epithelial for cisplatin. 
• An EMT signature may be a predictive marker in EGFR wild-type/KRAS wild-type patients with advanced stage NSCLC.  The authors analyzed the association between EMT signature and clinical outcome in patients enrolled in the BATTLE-1 trial but limited their analysis to patients whose tumors were WT for EGFR and KRAS.  Although the N is only 20, patients with disease control at 8 weeks (the primary study endpoint) showed a more epithelial-like signature as compared with those without disease control, although the difference is of borderline significance (P=0.05, by t test).  However, among the full group of 101 of 139 clinically evaluable patients (all treatment arms), expression of EMT signature genes was not prognostic of 8-week disease control or progression-free survival (PFS) in the overall group (all treatment arms).

This is a dense article but well-worth reading through in detail if you are interested in either EMT in NSCLC or mechanisms of EGFR-TKI drug resistance.  I offer a few further comments.

First, note that this is a study of NSCLC cell lines, so the findings have to be taken as hypothesis-generating for confirmation in clinical tumor specimens.  The limitations of studying cell lines ought to be well-known to you all.  But one point that has to be appreciated is that the phenomenon of EMT in vivo is context-dependent and critically depends on interaction with the tumor microenvironment--and this crucial fact is not and cannot be studied in this type of model.  Second, although it seems obvious to state this, histological subtype matters greatly with regard to EGFR mutations, EMT, and response to erlotinib.  Why do so many recently published studies still lump together non-small-cell lung cancer?  We recently focused exclusively on a group of patients with resected lung adenocarcinomas who received erlotinib upon disease progression in a study before the advent of EGFR mutation testing.  We identified two separate "epithelial" (high E-cadherin/low vimentin) and "mesenchymal" (low E-cad/high VIM) as well as intermediate/transitional tumors and found a trend toward worse DFS that did not quite reach statistical significance.  Unfortunately, our study was small (N=45) and I think that much larger numbers will be needed to show any importance difference.  In this study, out of 35 cell lines with adenocarcinoma histology, 29 (83%) had epithelial signatures, while 8 (23%) had mesenchymal signatures. Of 4 cell lines with squamous histology, there was an even distribution between epithelial and mesenchymal subsets.  Thus, the adenocarcinomas more commonly expressed an epithelial signature (P<0.0016, Chi-square test).  Finally, I have observed in our studies that EMT in vivo is a heterogenous process throughout a tumor.  Indeed, even if you focus on the invasive edge of a tumor, where one expects EMT to be occurring (as we did in a recently published abstract at AACR 2012), there is frequently significant variation in the expression and distribution of E-cadherin and vimentin.  What is the significance of this variation?  Can it be quantified and does the amount of variation in EMT have any prognostic or predictive significance?  Don't know--image analysis and quantitative immunohistochemical studies could possibly answer these questions. 

Impact of the Integrin Signaling Adaptor Protein NEDD9 on Prognosis and Metastatic Behavior of Human Lung Cancer

Thought this was an intriguing abstract. Signaling crosstalk between EGFR and integrins was a hot topic at AACC meeting earlier this year.




From Evernote:




Impact of the Integrin Signaling Adaptor Protein NEDD9 on Prognosis and Metastatic Behavior of Human Lung Cancer
Clipped from: http://clincancerres.aacrjournals.org/content/early/2012/10/19/1078-0432.CCR-11-2162.abstract?papetoc



Impact of the Integrin Signaling Adaptor Protein NEDD9 on Prognosis and Metastatic Behavior of Human Lung Cancer

Shunsuke Kondo1,Satoshi Iwata2, Taketo Yamada4, Yusuke Inoue7, Hiromi Ichihara3, Yoshiko Kichikawa2, Tomoki Katayose2, Akiko Souta-Kuribara2, Hiroto Yamazaki2, Osamu Hosono2, Hiroshi Kawasaki2, Hirotoshi Tanaka2, Yuichiro Hayashi4, Michiie Sakamoto4, Kazunori Kamiya5, Nam H. Dang8, and Chikao Morimoto6+
Authors' Affiliations: 1Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital; 2Department of Rheumatology and Allergy, Research Hospital, 3Division of Molecular Pathology, The Institute of Medical Science, The University of Tokyo; 4Department of Pathology, School of Medicine, 5Department of Pathology and Department of Surgery, Division of General Thoracic Surgery, School of Medicine, Keio University;
6Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University,
Tokyo; 7Department of Diagnostic Radiology, Kitasato University Hospital, Kanagawa, Japan; and 8Division of Hematology and Oncology, University of Florida Shands Cancer Center, Gainesville, Florida


Corresponding Author:
Chikao Morimoto, Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine,
Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Phone: 81-3-3868-2310; Fax: 81-3-3868-2310; E-mail: morimoto@ims.u-tokyo.ac.jp


Abstract

Purpose: In a substantial population of non–small cell lung cancer (NSCLC), expression and activation of EGF receptor (EGFR) have been reported and is regarded as a novel molecular target. A growing body of evidence has shown the signaling crosstalk between EGFR and integrins in cellular migration and invasion. NEDD9 is an integrin signaling adaptor protein composed of multiple domains serving as substrate for a variety of tyrosine kinases. In the present study, we aimed at elucidating a role of NEDD9 in the signaling crosstalk between EGFR and integrins.


Experimental Design: Using NSCLC cell lines, we conducted immunoblotting and cellular migration/invasion assay in vitro. Next, we analyzed metastasis assays in vivo by the use of xenograft transplantation model. Finally, we retrospectively evaluated clinical samples and records of patients
with NSCLCs.


Results: We showed that tyrosine phosphorylation of NEDD9 was reduced by the inhibition of EGFR in NSCLC cell lines. Overexpression of constitutively active EGFR caused tyrosine phosphorylation of NEDD9 in the absence of integrin stimulation. By gene transfer and gene knockdown, we showed that NEDD9 plays a pivotal role in cell migration and invasion of those cells in vitro. Furthermore, overexpression of NEDD9 promoted lung metastasis of an NSCLC cell line in NOD/Shi-scid, IL-2Rγnull mice (NOG) mice. Finally, univariate and multivariate Cox model analysis of NSCLC clinical specimens revealed a strong correlation
between NEDD9 expression and recurrence-free survival as well as overall survival.


Conclusion: Our data thus suggest that NEDD9 is a promising biomarker for the prognosis of NSCLCs and its expression can promote NSCLC
metastasis. Clin Cancer Res; 1–13. ©2012 AACR.



Footnotes

Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).



Received August 23, 2011.
Revision received August 20, 2012.
Accepted August 28, 2012.

©2012 American Association for Cancer Research.

Lack of NKX2-1 (TTF-1) expression in lung adenocarcinoma and EGFR mutations

My last post discussed one of the two papers I thought were notably in the October 2012 Journal of Thoracic Oncology. Here's my take on the other paper by Vincentin et al (J Thorac Oncol 2012;7:1522-1527). NK2 homeobox 1 is the "proper" name that we pathologists more affectionately call "TTF-1." NKX2-1 is normally expressed in type 2 pneumocytes and non-ciliated bronchiolar epithelial cells and has been shown to play an active role in sustaining lung adenocarcinoma. Since NKX2-1 is found in about 95% of lung adenocarcinomas with EGFR mutations, the authors studied whether NKX2-1 IHC staining is a useful provisional marker for guiding EGFR-TKI therapy in advanced stage lung adenocarcinoma while EGFR mutation analysis is being completed.

This is a large study including 810 consecutive NSCLC tumor specimens referred for routine diagnostic EGFR mutation testing. While one may debate the ultimate practicality of this study with respect to it's purpose, what recommends it to me is that the study population more closely mirrors what a general pathologist encounters in routine practice. The study includes biopsies (N=594), resections (N=162), and cytology specimens (N=54) and the overall incidence of EGFR mutations was 14%. It is important to note that the authors used the TTF-1 8G7G3/1 antibody clone for IHC testing. There are substantial differences between the different antibody clones for TTF-1 that have been recently noted in the literature and it is important to take note of this detail when analyzing articles that test NKX2-1 or determining the best antibody to use in your lab.

Results and Authors' Conclusions

NKX2-1 was evaluable in 98% of cases and was positive in 68%, negative in 32%. NKX2-1 positive immunostaining showed a strong correlation with EGFR mutations: in the EGFR-mutated cases, NKX2-1 was positive in 92% and negative in 8%. The probability of absent of EGFR mutation in all adenocarcinomas is 80%; in NKX2-1-negative adenocarcinomas that probability rises to 96%. The authors found a negative predictive value of negative NKX2-1 IHC for EGFR mutation to be >95%.

The authors conclude that if treatment is clinically urgent, the NPV of NKX2-1 expression is appropriate to use as a surrogate marker to choose conventional chemotherapy as starting treatment pending EGFR mutation analysis. The PPV of NKX2-1 is not sufficient to warrent adding an EGFR-TKI. Also, the result of NKX2-1 is not specific enough to exclude a specimen from EGFR-mutation analysis.

My take-aways

While the clinical situation in which NKX2-1 testing would influence an urgent treatment decision may uncommon, I think it is important to note this paper because when it does occur, the pathologist can play a vital role in assisting the clinician determine the management for such a patient. If one is following the diagnostic algorithm from the 2011 IASLC guidelines, one would not routinely test either histologically diagnostic adenocarcinomas or squamous cell carcinomas for NKX2-1 (TTF-1). Another point is that the SPT24 clone for TTF-1 is a more sensitive antibody for TTF-1/NKX2-1 (a point that the authors make as well) and, therefore, one would expect the percentage of NKX2-1-negative cases to be fewer and the NPV to be higher. Finally, the authors used direct sequencing of EGFR exons 19-21, followed by HRM screening, and PCR-sequencing for identifying EGFR mutations; another methodology could influence the denominator of EGFR-mutated cases and, thus, the predictive value of NKX2-1 IHC testing.

Loss of PTEN as a poor prognostic marker for lung adenocarcinoma

The October 2012 Journal of Thoracic Oncology presents two papers of interest to pathologists.

The first study is a paper by Yanagawa et al. that correlates PTEN expression with gene copy number, P53 expression, EGFR and KRAS mutations in surgically resected NSCLCs and examines the relationship between PTEN status, clinicopathologic characteristics and survival.

Recall that PTEN functions as a lipid phosphatase that negatively regulates the PI3K/AKT anti-apoptotic and proliferation pathway, which is a key downstream component of the EGFR pathway. Loss of PTEN is most commonly due to promoter hypermethylation, while homozygous deletion and nonsense mutations with LOH seem to be uncommon.

PTEN expression was examined by immunohistochemistry in a tissue microarray constructed from 152 patients with a median follow-up time of 2.3 years. The study consisted of 62% adenocarcinomas, 29% squamous cell carcinomas and 9% of tumors called “other.” Since this is a study of surgically resected patients, there is obviously an overrepresentation of stage one tumors compared to all patients typically diagnosed with lung cancer. Smokers comprised 79% of the study population. EGFR mutations were found in 15% and KRAS mutations and 22%. The authors defined loss of PTEN as complete absence of cytoplasmic staining in tumor cells.

Loss of PTEN was found in 63 out of 152 cases (41.4%). No significant differences were found between loss of PTEN and smoking, EGFR mutations, KRAS mutations, or p53 expression.

Patients with loss of PTEN expression had significantly worse disease-free survival compared with patients with retained PTEN expression (HR 1.76, log-rank p=0.038) but the prognostic effect was related directly to tumor histology: loss of PTEN was significantly associated with shorter DFS in adenocarcinoma only (HR 2.72, log-rank p=0.002). This association was also significant in multivariate analysis controlling for sex, age, histology and stage.

Recent data suggest that loss of PTEN may contribute to EGFR TKI resistance in NSCLC. PIK3CA mutations only account for 2% to 4% of NSCLC but loss of PTEN would result in constitutive activation of the PI3K pathway. This study suggests that lung adenocarcinomas selected for PTEN status may be susceptible to PI3KCA inhibitors that are currently under investigation.

My next post will discuss the other interesting paper in JTO this month.

Hypermethylation in non-small cell lung carcinoma

After an uncomfortably long hiatus from The Daily Sign-Out, I'm back. Nothing serious, just summertime distractions (fun!) and intense preparation for our lab's upcoming CAP inspection (not so fun). Anyway, here's an interesting item that I recently (re-) discovered under my stack of journals, papers, flotsam that I thought notable. Stayed tuned to this blog because I've collected some mighty interesting cases that I'll be sharing in the weeks ahead. Thanks for reading!

Methylation of any two of four genes — APC, RASSF1A, CDKN2A and CDH13 — in the tumor and draining lymph nodes is predictive of a poor prognosis in patients with stage I NSCLC and may identify a group of patients who might benefit from combined treatment with a low-dose DNA methyltransferase inhibitor and an histone deacetylase inhibitor (HDACI). You can get a free copy of the article by clicking here. There's also a nice accompanying podcast of the article if you're more of an aural learning (you know who you are). By the way, I love this journal! If you're interested in cancer, browse through the issues and I'm sure you'll find something to pique your interest.

Field cancerization though precancerous stromal changes

An important question in cancer research is the causes and mechanisms for the development of multifocal carcinomas, especially for non-small cell lung carcinomas (as I recently blogged on).  While a “field cancerization” effect has been postulated as a model for multifocal carcinomas for a long time, it remains enigmatic why cancers develop at one site and not another given that the entire “field” is presumably exposed to the same carcinogenic agent or stimulus.  More specifically, it is also obscure what the role is of the peritumoral stromal changes observed around multifocal carcinomas.  Are these changes a cause or consequence (or, more likely, both) of these tumors?  Under normal circumstances, the epithelial tissue stromal architecture imposes growth restraints upon epithelial structures and exerts a tumor-suppressive effect on “transformed” neoplastic cells.  A similar effect is observed in the metastatic process in which the vast majority of metastatic tumor cells fail to form tumors at distant metastatic sites.  The conventional view has been that the tumor stromal microenvironment is reactive in nature; that is, the tumor stroma develops as a result of molecular cues from the tumor itself.  A recent article in Cell (8 June 2012) by Bing Ho and colleagues presents data suggesting that the loss of mesenchymal Notch/CSL signaling causes stromal changes that are potent stimuli for the development of carcinomas (abstract).

Mice carrying a mesenchymal-specific deletion of CSL-RBP-Jk, a key effector in the Notch signaling pathway, develop spontaneous multifocal squamous cell carcinomas after dermal atrophy and chronic inflammation.  The authors found that CSL-deficient dermal fibroblasts promote increased tumor cell proliferation through upregulation of c-Jun and c-Fos expression.  This, in turn, was associated with higher levels of diffusible growth factors, inflammatory cytokines, and matrix-remodeling enzymes.

The authors then tested these findings with human skin biopsy specimens of multifocal actinic keratosis, a premalignant skin lesion for cutaneous squamous cell carcinoma strongly associated with sun exposure.  Stromal fields adjacent to multifocal actinic keratosis showed decreased Notch/CSL signaling, albeit only with exposure to UVA and not UVB exposure, through DNA methylation and epigenetic silencing of Notch signaling in dermal fibroblasts.  These findings imply that the phenomenon of field cancerization can be mediated through stromal alterations preceding the development of neoplastic epithelial clones—in other words, the stroma is precancerous due to mutagen exposure.

This model would be a fascinating one to pursue for future lung cancer research with both non-small cell and small cell lung cancers since these cancers are all also strongly associated with a known mutagenic exposure, are posited to develop from a field cancerization effect from this exposure, and are frequently associated with multifocal synchronous tumors.  Unfortunately, there isn’t exactly an analogous premalignant “actinic keratosis” lesion for NSCLC, at least one that can be easily recognize and sample, although I think such atypical adenomatous hyperplasia foci may be easier to study in mouse models.  Anyone interested in pursuing this, let me know! ; )

 

The New IASLC/ATS/ERS Lung Adenocarcinoma Classification

FYI-Excellent content for CME 
 
In 2011, the Journal for Thoracic Oncology published the "International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma," issued by a multidisciplinary team of lung cancer specialists.
 
To better understand the general implications of this new classification, and the issues affecting specific specialties, please join us in this series of webinars.


IASLC Experts Discuss Events
That Are Changing Clinical Practice

 
Module 1 - Introducing The New IASLC/ATS/ERS Lung Adenocarcinoma Classification
William D. Travis, MD
Memorial Sloan Kettering Cancer Center - NY, NY

Module 2 - Implications of the New IASLC/ATS/ERS Classification
Fred R. Hirsch, MD, PhD
University of Colorado Cancer Center - Aurora, CO
Paul Van Schil, MD, PhD
University Hospital of Antwerp - Edegem (Antwerp), Belgium
 
Module 3 - Highlights for the Pathologist
Ming S. Tsao, MD, FRCPC

Princess Margaret Hospital - Toronto, Ontario, Canada
 
Module 4 - Highlights for the Radiologist
Kavita Garg, MD
University of Colorado Cancer Center - Aurora, CO
 
Module 5 - Case Studies for the Practicing Clinician
Gregory Riely, MD, PhD
Memorial Sloan Kettering Cancer Center - NY, NY













This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the International Association for the Study of Lung Cancer (IASLC) and the University of Colorado School of Medicine. The University of Colorado School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

 

                       This activity is supported in part, by an educational grant from Eli Lilly and Company










 



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