Biology of Small Cell Lung Cancer: an Overview
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Eur Respir J REVIEW 1990, 3, 69~714 Biology of small cell lung cancer: an overview P. Weynants*, Y. Humbler••, J.L. Canon**+, M. Symann** Biology of small cell lung cancer: an overview. P. Weynants, Y. Humble!, JL. • Catholic University of Louvain (UCL), Dept of Canon, M. Symann. Pneumology, UCL Mont-Godinne Hospital, Yvoir, ABSTRACT: Despite disappointing results In the treatment of small cell Belgium. lung cancer (SCLC), major progress In our understanding of SCLC biology has occurred In the past decade. Advances in the technique for •• Oncology Unit, UCL St-Luc Hospital, Brussels, culturing SCLC tumours in vitro have greatly facilitated the study of the Belgium. biological properties of this tumour. The major progress in our understanding of SCLC Includes: 1) the availability of nonspecific biological tumour markers such as neuron-specific enolase (NSE), the BB ~ Research Assistant of the Fond National de lsoenzyme or creatine phosphokinase (CPKBB), bombesln/gastrln Recherche Scientifique (FNRS). releasing peptide (GRP) and chromogranln A; 2) the generation of monoclonal antibodies raised against the neural and epithelial features or SCLC tumours; 3) the Identification of several autocrine growth factors Correspondence: P. Weynants, Dept of Pneumology, such as bombesln/GRP, Insulin-like growth factor (IGF), transferrin and Mont-Godinne Hospital UCL, 5180 Yvoir, Belgium. physalaemin; 4) the close study of cytogenetic abnormalities leadlng to the discovery of a unique chromosomal deletion of the short arm of Keywords: Biology; genetic; small cell lung cancer. chromosome 3 (del 3p 1~21), and to changes In oncogenic expression, e.g. c-myc, L-myc and N-myc, accounting for known biological and treatment results. These data suggest that all lung cancers arise from a common stem Received: September, 1989; accepted after revision cell of endodermal origin. The Information derived from these biological December 21, 1989. studies represents the most promising avenue towards new treatment strategies In SCLC. Eur Respir J., 1990, 3, 699-714. Lung cancer remains the most common and lethal establishment of a large number of human SCLC human cancer in Western countries, showing a cell lines [9- 12]. continually rising incidence, especially among women This review will focus on recent progress in the [1, 2]. biology of SCLC (table 1), and outline the potential Small cell lung cancer (SCLC) accounts for 20-25% applications of these properties in the management of all new cases of bronchogenic carcinoma, but differs of SCLC patients. Indeed, at this time, information clinically and biologically from the other three major derived from biological findings represents the most histological types (squamous, adeno- and large cell promising avenue for a breakthrough in the treatment carcinomas), collectively referred to as non-SCLC. For of SCLC. non-SCLC, surgery remains the treatment of choice [1). Until 1970, surgery and radiotherapy were the SmaU cell lung cancer lines primary therapeutic modalities for SCLC, although the cure rate was less than 1%. Since then, "combina Establishment of SCLC cell lines tion chemotherapy" has become the cornerstone of therapy for SCLC, with an objective response achieved The studies on the biology of SCLC initially in almost 90% of SCLC patients [1, 2-{}J. However, necessitated the establishment of continuous cell lines despite this progress in tumour response and the from tumour specimens [10]. The major difficulty in resulting fivefold increase in survival duration, only 3- 5% culturing tumour cells is that normally they require of these patients are cured by the current the presence of serum which frequently encourages chemotherapeutic regimens [1, 2-5]. the overgrowth of non-malignant cells such as Although few important advances in the manage fibroblasts. ment of SCLC patients have occurred in the past Initial attempts to culture SCLC tumour cells decade, an explosion of new information on the basic using conventional culture media, were rarely fruitful cellular and molecular biology of this tumour has with a success rate of approximately 10% [9]. been discovered [7, 8). Much of this progress arises Subsequently, a success rate of 50% was reported, by from advanced cell culture methods leading to the using conditioned media from already established 700 P. WBYNANTS ET AL. Table 1. - Biological properties of SCLC and non-SCLC cell lines Characteristics Cell type SCLC NON-SCLC Classic Variant Growth morphology Tight aggregates Loose aggregates Adherent Cytology SCLC SCLC!LC Non-SCLC Doubling time ±72 h ±33 h ±50h Cloning efficiency 1-5% 10-30% 0.5-40% Radiation sensitivity Sensitive Resistant Resistant Blomarkers Peptide hormones ++ +/- LDDC ++ BN/GRP ++ NSE ++ + CPKBB ++ ++ Chromogranin A + + Growth factor receptors BN + IG!R + + ? Transfe~ + + + EGFR + Surface Ag. HLA class I ++ Leu7 + + Intermediate filaments Cytokeratin + + + Neurofllaments +I- + Oncogene amplification c-myc No Yes Sometimes N-myc Sometimes Sometimes No L-myc Sometimes ? No Chromosome abnormalities 3p deletion + + +I- This table summarizes the currently known biological properties of small cell carcinoma (SCLC) in comparison with non-small cell carcinoma cell lines (non-SCLC). LDDC: L-Dopa decarboxylase; NSE: neuron-specific enolase; BN/GRP: bombesin. gastrin releasing peptide; CPKBB: creatine-phosphokinase; EGFR: epidermal growth factor receptor; IGF: insulin growth factor receptor; HLA: histocompatibility locus antigen; SCLC!LC: small cell/large cell. SCLC cell lines. This suggested that growing SCLC the establishment of SCLC cell lines has a success rate cells produce necessary "mitogenic factors" absent of about 70% for all tumour containing specimens from conventional serum supplemented media [9]. prepared by experienced workers [15]. Nevertheless, after The NCI group following the lead of Sato [13, 14] selection of SCLC cell lines in HITES medium, the studied the replication of an established SCLC cell established cell lines grow better when they are line: "NCI - H69" in serum free medium sequentially maintained in conventional media containing 10% foetal supplemented with a large panel of "growth factors calf serum. and hormones". They were able to define the optimal In most cases, the original tumour specimens combination of factors permitting the most effective come from metastatic sites, including mainly pleural continuous replication of this cell line over a 12 month effusions, bone marrow aspirates or lymph nodes. period [11]. This supplemented RPMI medium is Only a few cell lines have been derived from the called HITES based on the added ingredients: primary tumour itself (10%). This could reflect an 8 1 hydrocortisone (10· M), insulin (15 Jlg·mi· ), intrinsic difference in the properties of these different 1 8 transferrin (100 Jlg·ml' ), 17 beta-oestradiol (10· M), tumoral locations [16], as well as the small number selenium (3·10·8 M). of viable cells obtained from endobronchial biopsies Subsequently, CARNEY et al. [14] demonstrated that (Crushing specimen). illTES medium can support proliferation of cells in Usually, SCLC cell lines retain a morphological, culture from both a fresh SCLC tumour specimen cytological and histological appearance similar to the obtained directly from patients or of heterotransplantcd original biopsy specimens from which they were SCLC tumour cells removed from nude mice. Currently, established [9, 17]. BIOLOGY OF SMALL CELL LUNG CANCER 701 Characteristics of established SCLC cell lines vasopressin (AVP), and calcitonin, may be detected in the serum of approximately 50% of untreated SCLC SCLC cell lines can be classified into two major patients, the level of these substances in the blood has groups, called "classic" and "variant" cell lines. never been correlated with either the stage of disease or Seventy percent of established SCLC cell lines retain the histological subtype [26, 27]. properties of differentiated neuroendocrine cells fr?m In recent years, considerable interest has the amine precursor uptake and decarboxylatiOn been generated in screening patient body fluids for (APUD) system. This includes the presence of those biological markers frequently detected in cytoplasmic dense core "neurosecretory granules" and SCLC cell lines or their culture supernatants. the expression of elevated levels of 4 biomarkers These markers would be useful for identifying, including the key APUD enzyme L-Dopa staging, monitoring treatment or predicting relapse decarboxylase (LDDC), the APUD enzyme neuron of SCLC patients [28]. However, none have been specific enolase (NSE), the peptide hormone bombesin shown to be either sensitive or specific enough to (gastrin-releasing peptide) (BN), and the BB use for screening asymptomatic patients [28]. Among iso-enzyme of creatine phosphokinase (CPKBB) [9]. "potentially useful markers", the four that have With few exceptions, these markers are not expressed been most extensively tested are NSE in non-SCLC cell lines. In addition, light (neuronspecific enolase), CPKBB (creatine microscopy demonstrates that SCLC lines retain phosphokinase), GRP (gastrin releasing peptide) and typical intermediate subtype morphology, they grow chromogranin A [29]. as tightly packed floating cellular aggregates, with lengthy doubling times and low colony forming efficiency in soft agar. These cell lines also remain NSE tumorogenic in nude mice. Enolase is a glycolytic enzyme that is widely The above characteristics defined the so-called distributed throughout mammalian tissues