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c-erbB-2/neu overexpression enhances metastatic potential of human lung cancer cells by induction of metastasis-associated properties

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Page 1: c-erbB-2/neu overexpression enhances metastatic potential of human lung cancer cells by induction of metastasis-associated properties

124 Abstracts/Lung Cancer 1.2 (1995) 113-160

subtypes was evaluated by in situ hybridization in 55 hmnan primary hunors shown to contain a high density of somatostatin receptors in binding assays. All 55 hunors expressed at least one SSTR subtype. Gf 55 somatostatin receptor- positive tumors, 46 had SSTR2 mRNA; all 46 were characterized as having receptors with a high aftlnity for the syuthetic adogue octreotide. of55 tumors, 12 expressed SSTRl, and 14 expressed SSTR3 mRNA. The subtype SSTRl was expressed alone in 4 cases, SSTR2 was expressed alone in 33 cases, and SSTR3 was expressed alone in one case. In 4 cases, all 3 SSTR were expressed simultaneously. The cases having SSTRl mRNA were identified in binding experiments with ‘~I-labeled somatostatin-14 and -28 analogues rather than with ‘l%[‘Qr’]-octreotide. Whereas meningiomas, neuroblastomas, pituitary adenomas, small cell lung carcinomas, lymphomas, and breast tumors expressed primarily a high abundance of SSTRZ, carcinoids, islet cell carcinomas, medullary thyroid carcinomas, and ovarian tumors had a mixed distribution of the somatostatin receptor subtypes. This is the first demonstration of the presence of SSTRl, SSTR2, and SSTR3 in primary human tumors using in situ hybridization. Since these somatostatin receptor, subtypes probably mediate distinct somatostatin actions, it may be worthwhile to search for subtype-specific analogues to use for the treatment and diagnosis of these tumors.

Effect of the dihydropyridiae dexniguldipine on the epidermnl gmwtb factor- stimulated pmliferntioo of human lung cancer cell lines Schuller HM, Orloff M, Reznik GK. Carcinogen./Devfl. Therapeul. Pmg., College of Veterinary Medicine, Universiv of Tennessee, Knoxville. TN 37909. Toxicol Wtro 1994;8:455-9. The dihydropyridine Dexniguldipine (B859-35) has been shown to inhibit calmodulin and protein kinase C in vitro, and has a significant therapeutic effect on induced neuroendocrine lung tumours in hamsters. As phase I clinical trials with this agent resulted in the development of stable disease in several patients with non-small-cell cancers and preliminary in vitro studies revealed several non-small-cc11 cancer cell lines susceptible to the antiproliferative effects of dexniguldipine, the possibility was investigated that this agent may inhibit cell proliferation stimulated by epidermal growth factor (EGF), which is expressed in many non-small-cell cancer types. Experiments conducted with six human lung cancer cell lines showed that dexniguldipine is a potent inhibitor of EGF-stimulated cell proliferation. This agent may therefore also be useful for the therapy of cancers that express the EGF receptor.

Cytogenetic findings in primary non-small cell lung cancer D’Akssandro E, Lo Re ML, Crisci R, Ligas C, Coloni GE Dipt di Med. Intema&nita Pubblica, Cat&&z di Genetica Medica, Universita degIi Studi, Ma S. Sisto 22/E, 67100 L ‘Aquik. Tumori 1994;80:151-6. Non-small ceil lung cancer (NSCLC) shows a complex cytogenetic

to characterize its malignant evolution. We therefore performed cytogenetic analyses of 20 primary NSCLC, 8 adenocarcinomas and 12 squamous cell carcinomas on direct preparations or short-term cultures. Only 1 case was analyzed after long-term culture. Results were obtained from 11 samples and clonal rearrangements were found in 3 cases, a diploid and a near-triploid clone with several aberrations such as i (9q), rob (14; 15) and rob (21; 21) in 1 case, a near-triploid clone in 1 case, aud Y chromosome loss in 1 case. Other aberrations found were sporadic, but + 7 aneuploidy and translocations involving lp were detected in 2

and 3 samples respectively. Although to date it has been very ditlicult to recognize primary changes in NSCLC, nevertheless a literature review and our results indicate that i (9q) and robertsonian translocations are relevant findings.

Physical map of small cell lung cancer deletion region on short arm of human chromosome 3 (3~13-22) based on radiation fusion hybrid analysis Siden TS, Golembieski W, Kumlien I, Rohme D, Smith DI. Division of Haematologv/Oncologx Department ofInternal Medicine, Wayne State Univ. School ofMedicine. Debwit, MI 48201. Somatic Cell MoI Genet 1994;20:121-32. Deletion of DNA sequences from various regions of the short arm of human chromosome 3 (3~13-14, 3~21, and 3~25) has been observed during the development of a variety of solid tumors, including lung and renal cell carcinomas. In this study we have used a set of radiation fusion hybrids to generate a physical map of chromosome 3p to orient the search for putative tumor suppressor genes. Eighty-six human- hamster radiation fusion hybrids were screened on Southern blots for the retention of 55 human chromosome 3p DNA markers. The high marker density enabled us to identity a set of successively overlapping chromosome fragments in the 3~13-22 area guided by eight markers with previously known order. ?iventy-four map intervals were suggested using breakpoints determined by partial fragment overlaps. The final order between the markers derived is consistent with previous information about lo&rations for 26 of the markers to three larger cytogenetic intetvals.

c+rbB--t/neu overexpression enhances metwtatic potential of human lung cancer cells by induction of metastasis-associated properties YU D, Wang S-S, Dulski KM, Tsai C-M Nicolson GL, Hung M-C Deparhnent of Tumor Biologv Texas Univ. M. D. Anderson Can. Ck, Box 79, ISI Holcombe Blvd.. Houston, i’X 77030. Cancer Res 1994; 54:3260-6. Previously, we and others have reported hi@ levels of expression of the c-erbB-2/neu gene in non-small cell lung cancer cell lines and primary tumors. We have also found that expression of c-erbB-2Ateuencoded p185(neu) was correlated with lymph node metastasis in lung squamous cell carcinomas. To investigate the potential role of the c-erbB-2/neu gene in lung cancer metastasis systematically, we introduced the human c-erbB-2/neu gene intovery lowpl85(neu)-expressing NCI-H460 human non-small cell lung cancer cells and then examined the experimental metastatic potentials among the parental NCI-H460 cells and stable transfectants with increased expression ofpl85(neu). Compared with the parental NCI-H460 cells, the NCIR460 transfectants ovemxprcssmg pl85(neu) produced si8nitlcantly more pulmonary and extrapulmonaty metastatic tumors in node mice. The changes in experimental metastatic potential in vivo were accompanied by increased invasiveness in vitro. In addition, important steps in the invasion and metastasis process, such as secretion of basement membranedegradative enzyme-s and migration through reconstituted basement membrane (Matrigel), were alsO increased in the NC&H460 transfectants overexpressing p185(neu): Moreover, scatming electron microscopy revealed that the p185(neu)- overexpressing NtXH460 tranfectants had signiticantly more microvilli and membrane protrusions than the parental cells, correlating with the increased invasive properties of these cells. The results dcmonsWate that overexpression of p185(neu) can enhance the experimental metastatic potential of NCI-H460 human lung cancer cellsly promoting invasion and the other steps in the memstatic cascade.