Biological heterogeneity of small cell lung cancer

Over the past 20 years considerable advances have been made in the characterization of the biologic properties of small cell lung cancer. The recognition that this histologic type of lung cancer, in contrast to the other major types of lung cancer, is highly sensitive to both chemotherapy and radiation therapy lead to significant improvements in the overall survival of patients with this disease. However, in spite of the initial major advances in therapy, overall results and survival have remained unchanged over the past 5 years. The majority of patients, although they will demonstrate an initial response to cytotoxic therapy, will ultimately die of their disease due to the development of drug resistance. Whether this development of drug resistance within a tumor cell represents the emergence of resistant clones of cells present at diagnosis, or a change within the cells exposed to cytotoxic therapy that renders them resistant to further therapy remains to be determined. The development of laboratory techniques that facilitate the culture and establishment of SCLC cell lines has greatly improved our understanding of the biology of SCLC, in addition to providing useful models for studies of mechanisms of drug resistance and metabolism. The ease of establishment of SCLC cell lines in defined medium suggests that these cells secrete "autocrine growth factors" essential for their growth in vitro. The characterization of these factors may provide an alternative means for treating this tumor in vivo. Moreover, by developing specific culture media for other types of lung cancer, similar advances in our knowledge of these tumors will occur. The established cell lines provide a model for studying mechanisms of drug and radiation sensitivity; and drug metabolism. The recognition that SCLC cell lines have elevated levels of L-dopa decarboxylase has lead to the development of specific agents that may alter the growth of these cells through inhibition of polyamine synthesis. Such specifically designed therapy may become important in the future therapy of these patients. The establishment of cell lines has clearly indicated the considerable heterogeneity that exists in SCLC. Although there have been several reports over the past 2 decades of the establishment {A table is presented} of individual cell lines of SCLC, general statements concerning the biologic properties of both SCLC and non-SCLC cannot be made. The use of defined culture conditions has greatly improved our ability to establish cell lines of SCLC from both a variety of different organ sites, and from treated and untreated patients. Detailed studies of these cell lines indicate that phenotypically they fall into two major categories, classic and variant SCLC lines (Table 7). It is likely that clinical correlates of these phenotypes exist, in particular, the variant phenotype. Radice et al and Hirsch et al have reported on the poor prognosis of patients who on histologic examination had a mixed small cell/large cell morphology (Fig 1C). The recognition that some variant cell lines were established from patients with this histologic subtype, and the demonstration that in vitro, variant cell lines have a much more "malignant" behavior suggests that patients with this phenotype would have a worse prognosis. Thus, it is likely that variant cell lines are the in vitro correlate of the mixed SCLC/LC histologic subtype. The origin of these variant cells remains unclear. Whether these cells represent a genetic drift from classic SCLC or indeed represent, de novo, a subtype of SCLC, remains unclear. Of the variant cell lines, two such lines have "arisen" in vitro after longterm passage of two classic SCLC cell lines. Such a change was associated with the loss of APUD cell characteristics and an amplification of the C-myc oncogene. These data suggest that some SCLC may undergo a time-dependent change in biologic characteristics that has important clinical and therapeutic implications. However, as many variant cell lines express this phenotype at the outset it is also possible that in some instances they may arise de novo in vivo. The accumulation of clinical and biologic data on SCLC has clearly demonstrated that SCLC is not a single disease entity but a spectrum of diseases with different behaviors and prognoses. The range of different biologic properties that can be present in these tumors appears to be of clinical importance and suggests that the evaluation of the biologic characteristics of individual tumors may become an important future requirement in the staging and management of patients with small cell lung cancer.