Induced morphological changes in human small cell lung carcinoma cells.

Several theories suggest that lung carcinomas are not totally separate entities, but are derived from a common precursor, probably of endodermal origin. The histological classification of lung cancers is complex, with much overlap between groups broadly designated as small cell (SCLC), squamous cell, adenocarcinoma and all others simply termed non-small cell. It is shown here that in vitro exposure of classic, non-adherent SCLC lines to 10 microM 5' bromodeoxyuridine (BrdU) results in a rapid cell-line dependent change to a morphology consistent with an adherent, non-small cell phenotype. Accompanying this morphological shift is a decreased expression of the amplified N-myc protooncogene. These induced changes underline the morphological relatedness of lung carcinoma cell lines.     

Neurotensin in human small cell lung carcinoma

High levels of neurotensin-like immunoreactivity were found in human small cell lung carcinoma lines. No immunoreactivity was present in non-small cell carcinoma lines and only low amounts in postmortem human lung tissue. The immunoreactive material co-eluted with synthetic neurotensin on two different chromatographic systems. No evidence was obtained for the presence of specific neurotensin binding sites in any of the small cell carcinoma lines examined. The results suggest that small lung cell carcinoma lines may be useful for studying the biosynthesis of human neurotensin.     

Comparative proteomics of small cell lung carcinoma

Small cell lung carcinoma (SCLC) is an aggressive, highly metastatic cancer with a strong tendency for chemotherapy resistance. Identification of proteins uniquely expressed in SCLC cells, can facilitate the development of new diagnostic tools, improve immunotherapy, and deepen our understanding of the underlying mechanisms of the disease. Here we describe a comparative proteomics analysis of ten SCLC cell lines and three controls lines, while searching for proteins preferentially expressed in SCLC cells as potential disease markers. Total protein extracts were compared by two-dimensional gel electrophoresis and by two-dimensional liquid chromatography resulting in the identification of 1093 proteins, 202 of which were detected only in the SCLC cells. These include proteins of different cellular functions, including cellular proliferation and known tumor antigens. Since SCLC has a neuroendocrine origin, of major interest are the identified proteins involved in nerve and brain embryonic development. These proteins are potentially valuable as both tumor markers and as antigens for immunotherapy.     

Leptomeningeal metastases from small cell lung carcinoma

BACKGROUND: The current study was performed to investigate the frequency of leptomeningeal metastases (LMM) in patients with small cell lung carcinoma (SCLC) as well as the effect of LMM on survival, any correlation between the location of the LMM and survival, and a possible increased risk of LMM among patients with brain metastases (BM) located in the posterior fossa. METHODS: Between 1980-2003, 458 consecutive patients with SCLC were enrolled in the current study. Patients underwent regular neurologic examination and imaging of the brain before, during, and after treatment. The diagnosis of LMM was established by either the presence of malignant cells in the cerebrospinal fluid or positive clinical symptoms and signs supported by radiologic findings on magnetic resonance imaging. RESULTS: The group of patients in the current study had a 2% prevalence of LMM and the 2-year cumulative incidence of LMM was found to be 10%. The median survival after the diagnosis of LMM was reported to be 1.3 months. The median survival among patients with LMM located in the spinal cord was 2.4 months. The reported LMM-free survival 2 years after the diagnosis of SCLC was 78% for patients without BM and 61% for those patients with BM. Approximately 15% of the patients with BM located in the posterior fossa developed LMM, whereas only 10% of patients with cerebral BM did. CONCLUSIONS: The current prospective study found a 2-year cumulative incidence of LMM of 10%, with a prevalence of 2%. Patients with LMM located in the spinal cord appeared to survive longer than patients with cranial LMM. SCLC patients with BM located in the posterior fossa may be at a higher risk of developing LMM compared with patients with cerebral BM.     

DNA ploidy in small cell carcinoma of the lung

Fluorometric single cell DNA analysis was performed on 123 tumour samples from 33 patients who had died of small cell carcinoma of the lung (SCCL). In 36% (12 patients) the modal DNA profile was hypodiploid or near diploid and the median survival time was 16.3 months, as opposed to 9.5 months for the 21 patients with hyperdiploid DNA profile, who also seemed to have a lower response rate to chemotherapy. It is suggested that an estimation of the modal DNA ploidy before the start of the treatment in SCCL might be used as a cellular parameter to obtain more comparable treatment study groups and for the prediction of survival.     

Prognostic factors in patients with small cell lung carcinoma

Background The current prognosis in patients with small cell lung cancer (SCLC) is unsatisfactory, even though there have been considerable improvements in diagnosis and treatment. Methods We retrospectively analyzed all consecutive patients with small cell lung carcinoma between 1995 and 2007 in a Turkish chest hospital. A total of 116 SCLC patients initially presented with limited disease, while 92 small cell lung carcinoma patients were found to be extensive. Results The mean age of the patients (18 women and 190 men) was 56 years. The median survival was 74 weeks. Performance status, superior vena cava syndrome (SVCS), stage, elevated white blood cell count, elevated lactate dehidrogenase levels, short symptom duration (≤4 weeks) response to chemotherapy and bone metastasis were significant prognostic factors in univariate analysis. It was necessary for patients to receive at least three cycles of chemotherapy for a survival benefit. Cox proportional hazards model identified only stage, performance status and SVCS as independent prognostic factors. Conclusions Stage, performance status and SVCS were determined to be the most important prognostic factors for SCLC patients.     

Genetic characterization of lung metastases in renal cell carcinoma

Prognosis of patients with renal cell carcinoma (RCC) is mainly determined by metastases. The understanding of the metastatic process will give the basis for a differential diagnosis leading to an individual prognosis and to new therapeutical strategies. In order to define specific genetic alterations which are common in renal cancer metastases of the lung, we performed comparative genomic hybridization (CGH) on metastases and in some cases on their related primary renal tumors. For CGH, DNA was isolated from 2 or 5 paraffin sections (5 micro m). Tumor and normal (control) DNAs were amplified by DOP-PCR and labeled with biotin-dUTP and digoxigenin-dUTP, respectively. Hybridization and detection were carried out according to standard protocols. In 33 out of 40 metastases, genetic alterations were detected, most frequently these were losses of chromosomes 3p (74%), 8p (31%), 9 or 9q (34%), 14 [26%, 18q (40%) and gains of chromosome 5/5q 34%], 7 (31%) and 12 (26%). Combination of loss of 8p and gain of 8q occurred frequently. The mean number of aberrations per tumor was 8.1 (1-11). The comparison of alterations in related primary and metastatic tumors showed identical alterations in 5 out of 8 cases. This study demonstrates, that lung metastases from renal cell carcinoma are characterized by an accumulation of specific genetic alterations which show a clonal relationship to the related primary tumors.     

Long-term survival in small cell carcinoma of the lung

We analyzed the long-term survivors in a group of 255 patients with newly diagnosed small cell carcinoma of the lung (SCCL) between January 1978 and July 1983. Long-term survivors were defined as those patients free of cancer 2 years after initiation of therapy. Only 6 patients (2.5%) were free of disease at this time. Two patients relapsed at 29 and 40 months from the start of chemotherapy. Both patients were retreated with chemotherapy, and one of them achieved a complete response. Despite the increase in median survival in SCCL with chemotherapy over the past 10 years, long-term prognosis remains very poor employing standard treatments.     

Pathology of small cell carcinoma of the lung

Small cell carcinoma of the lung is one of the major subtypes of primary lung cancer. It is a highly aggressive lethal neuroendocrine carcinoma. It is closely related to other neuroendocrine carcinomas of the lung, including carcinoid, atypical carcinoid, and large cell neuroendocrine carcinoma. This article discusses the classification of small cell carcinoma of the lung, identifies its cytologic and histologic characteristics, and places it in context with the other neuroendocrine carcinomas of the lung.     

The small GTPase RhoA has greater expression in small cell lung carcinoma than in non-small cell lung carcinoma and contributes to their unique morphologies

The two major forms of lung carcinoma, small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC), are clinically distinct, and are also differentiated by morphology and behavior in culture. SCLC cells have a greater metastatic potential than NSCLC cells in vivo, and exhibit a unique spherical morphology in culture due to their inability to adhere and spread on the substratum. Because the small GTPase RhoA affects metastatic properties and regulates cell morphology, we examined whether differences in RhoA expression and activity contribute to the distinct SCLC and NSCLC phenotypes. We found that the expression and GTPgammaS-dependent activation of RhoA are generally greater in SCLC cell lines (SCC-9, NCI-H69, NCI-H146, and NCI-H345) than in NSCLC cell lines (NCI-H23, NCI-H157, NCI-H520, and NCI-H522). The effects of inhibiting Rho-mediated signaling in these cells were investigated by transfecting the cells with cDNA coding for C3 exoenzyme, which ADP-ribosylates and inactivates Rho. Expression of C3 exoenzyme in SCLC cells induces cell-cell compaction, and causes NCI-H345 cells to adhere and spread on collagen IV. In contrast, expression of C3 exoenzyme in NSCLC cells does not induce detectable compaction, but induces cell spreading of NCI-H23 and NCI-H157 cells. Cell proliferation is diminished by Rho inactivation in the majority of the NSCLC cell lines, but not the SCLC cell lines. Expression of p21Cip1/WAF1 is also diminished by Rho inactivation in two of the SCLC cell lines, but is not significantly altered in the NSCLC lines. These results indicate that Rho-mediated signaling may regulate different events in SCLC and NSCLC cells, including adhesion of SCLC cells and proliferation of NSCLC cells.     

Bone marrow evaluation in small cell carcinoma of the lung

Bone marrow examination is commonly included in the staging of small cell lung carcinoma (SCLC). We reviewed marrow samples of 103 patients. Marrow examination was mainly performed by unilateral or bilateral biopsy of iliac crests, using a Jamshidi needle. Only 6 of 97 evaluable cases (6.2 per cent) were positive for marrow metastases at staging, and in 3 cases (3 per cent) bone marrow was the only metastatic site. No focal metastases were found in additional sections made from the blocks of negative samples. In our experience bone marrow biopsy was of little value in staging SCLC. Bilateral biopsy plus aspirate, with the addition of more sophisticated staining techniques might, however, provide a higher yield of positive marrow involvement.     

Spinal cord metastasis in small cell carcinoma of the lung

Among 50 patients with small cell bronchogenic carcinoma who were placed on a protocol of combined chemotherapy and radiation therapy, seven patients developed recurrence in the spinal cord. Five cases terminated in paraplegia and death. One patient with pontine recurrence recovered with local radiation therapy. One patient, diagnosed early, responded to local radiation therapy and is ambulatory. Methods of diagnosis were myelogram, computerized axial tomography, cerebro spinal fluid, chemistry and cytologies. The poor prognosis and the difficulty of diagnosis suggest that we should evaluate prophylactic therapy of the entire cranio-spinal axis.     

Biosynthesis of procalcitonin in small cell carcinoma of the lung

Immunoreactive calcitonin (CT) secreted by DMS 53, a cell line derived from human small cell carcinoma of the lung, consists almost entirely of molecular species larger than the mature hormone (Mr 3,420). Messenger RNA isolated from DMS 53 cells and nude mouse tumors was translated in wheat germ systems, and the products were precipitated with CT-specific antisera. Analyses of the translation products by electrophoresis on 15% polyacrylamide-sodium dodecyl sulfate gels indicated synthesis of a Mr 16,500 preprohormone that was reduced to Mr 14,500 by cotranslation with microsomal membranes. Immunoprecipitation of CT from media from pulse-labeled cultures revealed two major products (Mr 16,500 and Mr 14,500) and up to three minor secreted polypeptides (Mr 9,400, 8,400, and 6,800). Intracellular CT from cell homogenates appeared almost entirely as a single major product (Mr 14,500) and possibly 3-4 minor components (Mr 16,500; 9,200, 8,400, and 6,800). No glycosylated forms of CT were demonstrable by lectin binding methods or labeling attempts with tritiated sugars. The presence of multiple CT species in DMS 53 cells suggests significant post-translational processing of the larger precursor molecules and the accumulation and secretion by small cell carcinoma of the lung of several intermediate immunoreactive forms via a glycosylation-independent secretory pathway.     

Endocrine function in small cell undifferentiated carcinoma of the lung

The endocrine status of 106 patients with undifferentiated small cell carcinoma of the lung was evaluated before treatment was begun. Almost one half of the patients had evidence of abnormal control of the secretion of adrenal cortical steroids, manifested by loss of diurnal rhythmicity or dexamethasone suppressibility. Only two had the clinical syndrome of ectopic ACTH secretion. Evidence of inappropriate secretion of vasopressin was found in 38% of the patients, most of whom also had abnormalities of corticosteroid secretory pattern. About one half of the patients had evidence of abnormal glucose tolerance, and many also had a paradoxical rise of plasma growth hormone concentration after glucose administration. The levels of the other hormones studies were normal. The pattern of hormone abnormality observed in these patients appears to be relatively specific for small cell undifferentiated carcinoma, and is different from that observed in other pulmonary tumors. Patients with abnormal control of plasma cortisol had a worse prognosis than those with normal adrenal function, largely because of decreased response rates to chemotherapy. Other endocrine abnormalities were of no prognostic significance.