Lung cancer is the commonest cause of cancer death in the United States (1
). Of these, approximately 15–20% of cases are SCLC, a highly aggressive, primitive neuroendocrine tumor that is often widely metastatic at the time of diagnosis. Most cases of SCLC are initially sensitive to cytotoxic chemotherapy, despite the fact that most of these tumors lack both p53 and pRB, and manifest overexpression of BCL2 (2
). Regimens based on cis-platinum, usually in combination with etoposide, result in robust and often dramatic clinical responses in SCLC patients (3
). Despite the effectiveness of this drug combination, the overwhelming majority of SCLC patients succumb to a chemoresistant recurrence within 2 years of diagnosis (3
). Neither the use of novel chemotherapeutics, nor the introduction of dose intensification regimens have improved survival, which has remained essentially unchanged for the last 30 years (3
). The clinical imperative in SCLC is the discovery of novel strategies to prevent disease recurrence.
For three decades, the mainstay of preclinical cancer therapeutic research has been the use of human cancer cells lines cultured in vitro
, and xenografts derived from these cell lines grown in vivo in immunodeficient mice. Neither of these models consistently predict efficacy in clinical trials, resulting in two major barriers to the successful translation of new cancer therapeutics. First, resources are expended on drug development based on these models that ultimately fail in clinical trials. Secondly, many potentially useful therapies that might be beneficial in humans are discarded because they fail to show efficacy in conventional cell culture and xenograft models. Emerging evidence suggests that the process of establishing conventional cell lines from human cancers results in distinct and irreversible loss of important biological properties, which include (i) gain or loss of gene amplification (4
), (ii) the ability to migrate and metastasize (6
) (iii) the maintenance of a distinct stem cell population (6
) and (iv) the preservation of dependency on embryonic signaling pathways (7
). In all cases, these properties are not restored when these conventional cell lines are grown as heterotopic or orthotopic xenografts.
Preclinical modeling of SCLC chemotherapy presents challenges in addition to those outlined above. Since SCLC is usually diagnosed by endobronchial biopsy or fine needle aspiration cytology (FNAC), substantial quantities of fresh or frozen tissues are typically lacking in most tumor banks. For this reason, most SCLC research relies on conventional cell lines, which are often chemoresistant, since they were derived from patients who had received cytotoxic chemotherapy (9
). In addition, all of these cell lines suffer from the experimental limitations outlined above, and lack the three dimensional tumor-stromal interactions which appear to significantly affect the response of these cells to chemotherapy (10
). As part of our ongoing efforts to develop better models for the study of SCLC, we generated and characterized a series of primary xenograft models derived from chemo-naive patients in order to more accurately model this disease. In our first description of this primary xenograft model, we showed that differential expression of BCL2 in vivo
was correlated with growth responses to the BCL2 inhibitor ABT-737 (11
). Here, we describe a detailed gene expression analysis of this model that reveals how gene expression is irreversibly altered during the process of establishing conventional cell culture, and how maintenance of SCLC xenografts passaged exclusively in vivo
can retain features of the primary tumor of direct relevance to preclinical drug testing.