4th LTBW Abstracts/Lung Cancer 10 (1994) 347-373 361

those patients with Stage 11 disease, the survival of the BGAA- negative group was shorter (P = 0.048), with a median survival of 11 months versus 53 months for the BGAA-positive group. Recently, Miyake et al. reported that expression of a blood- group antigen H-related carbohydrate antigen was an impor- tant prognostic factor in patients with NSCLC (N Engl N Med 1992; 327: 14). The 5-year survival rate was 20.9% in the antigen-positive group and 58.6% in the antigen-negative group. For the study population overall, antigen positivity was the most important prognostic factor, followed by N stage and T stage. These results are quite exciting, not only because the antibody they used (i.e., MIA-15-5 antibody) recognizes H/Ley/Leb antigens which accumulate in tumors negative for blood-group antigens A and B, indirectly confirming previous results, but also because this antibody has shown strong in- hibitory effects on cell motility and the potential for metastasis. These Endings clearly support the idea that cell surface carbo- hydrate structures play an important role in tumor progression and heterogeneity. Furthermore, this MIA-15-5 antibody was found to bind to a receptor for an autocrine motility factor, providing a clue to the biologic consequences of altered expres- sion of blood-group antigens in tumor cells. It would be of fur- ther interest to examine the BGAA-negative cell lines to better understand the underlying biologic mechanisms that may be useful for future design of therapy and prevention strategies.

Peripheral airway cell differentiation in neoplastic and non- neoplastic lung Linnoila RI. Biomarkers and Prevention Research Branch, National Cancer Institute, NIH, Rockville, MD 20850.

There has been an increase in the incidence of lung adenocar- cinemas in the United States. While these tumors are a heterogenous group, in our experience one half of all pulmo- nary adenocarcinomas demonstrate features suggesting an ori- gin from peripheral lung. They are thought to originate from metaplastic mucin producing cells or peripheral airway cells, including bronchiolar non-ciliated secretory cells (Clara cells), and alveolar Type II cells. Clara cells and Type II cells are pro- genitor cells also for the non-neoplastic pulmonary epithehum. We have used two well-defined proteins produced by these cells, the Clara cell IO-kDa protein (CCIO) and the major sur- factant associated protein A (SPA), to study the role of peripheral airway cell differentiation in human lung car- cinogenesis.

Immunohistochemistry (IHC) revealed CC10 reactivity in the cytoplasm of nonciliated secretory cells throughout the con- ducting airways. Epithelial basal cells, and alveolar cells were negative. The expression of mRNA paralled the expression of protein. Most abundant mRNA was seen in bronchioli. In the presence of atypia, CC10 expression decreased in bronchi, and became detectable in up to 20% of alveoli at both mRNA and protein level. Changes were minimal in bronchioh. The extent of the atypia, including fibrosis, squamous metaplasia, alveolar epithelialization, dysplasia, and hyperplasias of basal, goblet, and type II cells correlated with smoking history. By IHC SPA was detected in alveolar Type II cells, and macrophages. Stain- ing was cytoplasmic. SPA mRNA expression was detected in scattered alveolar Type 11 cells, and rare cells in the conducting

airways. In the presence of atypia, increased expression of SPA both at protein and mRNA level was seen in clusters of reactive Type II cells around alveoli. These cells were frequently posi- tive for markers of proliferating cells, overexpressed c-myc but lacked ~53 immunoreactivity.

By IHC, up to 40% of adenocarcinomas followed by large cell (25%) and squamous cell carcinomas (16%) were positive for CC10 and/or SPA. Staining was mostly focal, and less in- tense than in non-neoplastic lung. Focal expression of SPA mRNA was detected in 5119 and CC10 mRNA in l/19 tumors by in situ hybridization. Expression of SPA was associated with female gender and lighter smoking history; CC10 with younger age. In a subset of earlier stage patients, SPA and CC10 expres- sion was of prognostic significance.

We also examined a panel of well characterized NSCLC cell lines for the expression of peripheral airway cell markers. Twenty-eight out of 52 (54%) cell lines expressed mRNA for SPA and/or CClO, but there was a poor correlation with the presence of characteristic ultrastructural features such as lamellar bodies or electron dense granules. The expression, as analyzed by RNA-RNA in-situ hybridization, was often focal, and 13 cell lines were positive for both markers.

We conclude that the two markers are expressed at high cellular levels in non-neoplastic lung, and the expression is decreased in neoplastic lung. Atypia is associated with altered marker expression evidenced by deviations from expected dis- tribution patterns.

Small cell lung cancer differentiation: Oocogene modulation by all-trm-retinoic acid Mabry M, Kalemkerian G, Jasti R. The Johns Hopkins On- cology Center, 424 North Bond Street, Baltimore, IUD 21231.

The precise determinants of tumor progression and treat- ment resistance in small cell lung cancer (SCLC) are unknown. However, one component may be the movement of the SCLC phenotype along a differentiation continuum, linking SCLC to the non-small cell lung cancer (NSCLC) tumors [l]. Clinical support for this concept comes from studies which have demonstrated a 25-40% prevalence of conversion from SCLC to a NSCLC phenotype during therapy [2]. Based on this paradigm; we developed a laboratory model of SCLC progres- sion using genetic manipulations to induce transition from a SCLC to a NSCLC phenotype [3,4].

Our model features the genetic manipulation of SCLC cells so that they acquire features of NSCLC. This model involves the insertion of genes which appear, based on phenotypic segre- gation, to be candidates for driving the transition process. A mutated ras gene was chosen because many NSCLC, but not SCLC, tumors have ras mutations [5) and exhibit increased ex- pression of p21 la’ proteins [6]. Insertion of the mutant v-rasH gene into SCLC cells which overexpress the c-myc (NCI-H82) or N-myc (NCI-H249) gene product, induces acquisition of NSCLC features [3,4]. This transition from a SCLC to a NSCLC phenotype is associated with increased growth rate, loss of neuroendocrine marker expression, acquisition of epithelial marker expression, such as CEA, cytokeratin and desmosomes, and acquired resistance to polyamine depletion via difluloromethylornithine (DFMO) [3,4]. This directly con-