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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Large cell neuroendocrine carcinoma (LCNEC) of the lung is defined as a poorly differentiated and high-grade neuroendocrine tumor that is morphologically and biologically between atypical carcinoid and small cell lung carcinoma (SCLC). During a survey concerning bcl-2 protein expression in the subtypes of lung cancer, we noticed that two previously diagnosed non-SCLCs met the criteria for LCNEC. Because LCNEC is a newly recognized clinicopathologic entity and because all reported cases have been retrieved from the so-called "neuroendocrine tumor file," we suspected that LCNEC had been underdiagnosed. In the present study, we histologically reviewed 766 surgically resected lung cancers and were able to diagnose 22 (2.87%) LCNECs with the neuroendocrine features subsequently confirmed by immunostaining for multiple neuroendocrine markers. Each case stained positively for at least three general neuroendocrine markers, and 12 (54.5%) also were positive for neuroendocrine hormones. Histologically, most LCNECs showed a marked decrease in or a loss of organoid architecture and could be mistaken for poorly differentiated adenocarcinoma or squamous cell carcinoma. Because our LCNECs are the first to be identified by retrospective review of routinely diagnosed lung cancers, and 18 had been classified as non-SCLC, they may represent cases relatively difficult to diagnose. The present study shows that the most difficult diagnostic factor of LCNEC is the recognition of its light microscopic neuroendocrine features, and LCNEC must be distinguished not only from atypical carcinoid or SCLC, but also from common non-SCLC. Histologically, when an organoid architecture is subtle or absent, the rosettelike structure becomes the best marker for the recognition of neuroendocrine differentiation. Clinically, the prognosis for our LCNECs was significantly worse than that for stage-comparable non-SCLCs (p = 0.046).
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PMID:Large cell neuroendocrine carcinoma of the lung: a histologic and immunohistochemical study of 22 cases. 959 21

The 5-year survival rate of non-small cell lung carcinoma (NSCLC) has only marginally improved during the past two decades, despite advances in surgery and chemoradiotherapy. Major efforts are currently directed toward biological characterization of these tumors to define biomarkers able to add further prognostic information, thus improving new therapeutic protocols. We analyzed the predictive relevance of the microvessel count (MC), bcl-2 and p53 proteins, proliferative activity, and usual postsurgical parameters on recurrence and overall survival in a series of 70 patients with NSCLC. The expression of biological parameters (p53, bcl-2, proliferative activity, and MC) was detected using immunohistochemistry on paraffin-embedded and frozen sections from the tumors treated with surgical resection alone until relapse. In the univariate analysis, the histotype, tumor status, node status, p53, bcl-2, and MC have been shown to significantly affect progression and death. In the multiple logistic regression analysis, the MC (P < 0.000001), tumor status (P < 0.005), and node status (P < 0.0002) influenced the overall survival while prediction of relapse was strongly revealed by tumor status (P < 0.005), nodal metastatic involvement (P < 0.000001), and the assessment of the vascular count (P < 0.0004). These data have allowed the creation of a multivariate model which may add more information on risk of recurrence and death in patients with NSCLC and can form the basis for future randomized clinical trials.
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PMID:Recurrence and death in non-small cell lung carcinomas: a prognostic model using pathological parameters, microvessel count, and gene protein products. 981 69

A high level of apoptotic activity and an independence of apoptosis from the expression of p53 and bcl-2 have been observed in non-small-cell lung carcinoma. We examined 44 samples of normal, metaplastic and premalignant (i.e. mild, moderate and severe dysplasias and carcinoma in situ) bronchial epithelia to evaluate whether differences in the apoptotic activity could already be seen in the stages preceding squamous cell carcinoma of the lung (SQCLC). Apoptotic cells and bodies were visualized by 3' end labelling. The expression of p53 and members of the bcl-2 gene family, such as bcl-2, bax and mcl-1, were determined immunohistochemically with specific antibodies. The relative number of apoptotic cells and bodies [apoptotic index (AI%)] was already increased threefold as the normal bronchial epithelium changed to squamous metaplasia, and the AIs of the dysplastic lesions were about four times higher than those of the normal epithelium. Apoptosis was significantly associated with cell proliferation, as determined by proliferating cell nuclear antigen (PCNA) immunohistochemistry. However, the extent of apoptosis did not correlate with the expression of p53, bcl-2, bax and mcl-1. We conclude that, in the metaplasia-dysplasia-carcinoma sequence in the lung, the elevation of the AI% is an early event associated with cell proliferation activity, but is independent of the expression of p53, bcl-2, mcl-1 and bax.
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PMID:Apoptotic activity is increased in parallel with the metaplasia-dysplasia-carcinoma sequence of the bronchial epithelium. 1007 Sep 3

Small cell carcinoma is a rare neoplasm in the esophagus. To evaluate cell proliferation activity and its underlying mechanisms in this tumor, we examined immunohistochemically 5 cases of small cell carcinoma of the esophagus (SCCE) for expressions of tumor suppressor proteins, oncoproteins and cell proliferation markers including p53, p21WAF1/CIP1, retinoblastoma (Rb) protein, bcl-2, Ki-67 and PCNA, and compared the results with those of 5 cases of small cell carcinoma of the lung (SCCL) and 10 cases of squamous cell carcinoma of the esophagus (SQCE). The prevalence and labeling index of p53-immunoreactivity tended to be higher in SCCE (4/5; 56.6%) and SCCL (4/5; 79.9%) than in SQCE (6/10; 48.8%). Expression of p21WAF1/CIP1 was observed in 2 of 10 cases of SQCE. In contrast, its expression could not be detected in any cases of SCCE and SCCL examined. Expression of Rb protein was observed in 9 out of 10 cases of SQCE, but not in any cases of SCCE and SCCL. SCCE and SCCL showed more frequent and intense immunoreactivity for bcl-2 than SQCE. In expression of cell proliferation markers (Ki-67 and PCNA), no remarkable difference was observed among SCCE, SCCL and SQCE. These results suggest that SCCE and SCCL could share some genetic alternations including mutation of p53, loss of Rb gene and overexpression of bcl-2, and these may be related to the similar biological potentials between the two. Furthermore, SCCE was different from SQCE in expression of Rb protein and bcl-2, and these two types of esophageal carcinoma could arise through different molecular mechanisms.
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PMID:Immunohistochemical analysis for cell proliferation-related protein expression in small cell carcinoma of the esophagus; a comparative study with small cell carcinoma of the lung and squamous cell carcinoma of the esophagus. 1021 9

Programmed cell death (PCD) is a genetically regulated pathway that is altered in many cancers. This process is, in part, regulated by the ratio of PCD inducers (Bax) or inhibitors (Bcl-2). An abnormally high ratio of Bcl-2 to Bax prevents PCD, thus contributing to resistance to chemotherapeutic agents, many of which are capable of inducing PCD. Non-small cell lung cancer (NSCLC) cells demonstrate resistance to these PCD-inducing agents. If Bcl-2 prevents NSCLC cells from entering the PCD pathway, then reducing the amount of endogenous Bcl-2 product may allow these cells to spontaneously enter the PCD pathway. Our purpose was to determine the effects of bcl-2 antisense treatment on the levels of programmed cell death in NSCLC cells. First, we determined whether bcl-2 and bax mRNA were expressed in three morphologically distinct NSCLC cell lines: NCI-H226 (squamous), NCI-H358 (adenocarcinoma), and NCI-H596 (adenosquamous). Cells were then exposed to synthetic antisense bcl-2 oligonucleotide treatment, after which programmed cell death was determined, as evidenced by DNA fragmentation. Bcl-2 protein expression was detected immunohistochemically. All three NSCLC cell lines expressed both bcl-2 and bax mRNA and had functional PCD pathways. Synthetic antisense bcl-2 oligonucleotide treatment resulted in decreased Bcl-2 levels, reduced cell proliferation, decreased cell viability, and increased levels of spontaneous PCD. This represents the first evidence that decreasing Bcl-2 in three morphologically distinct NSCLC cell lines allows the cells to spontaneously enter a PCD pathway. It also indicates the potential therapeutic use of antisense bcl-2 in the treatment of NSCLC.
Lung Cancer 1999 Feb
PMID:Antisense bcl-2 treatment increases programmed cell death in non-small cell lung cancer cell lines. 1021 15

The biologic characteristics of the two human giant-cell lung carcinoma strains with high (strain D) and low metastatic potential (strain C) were studied, including karyotype of chromosome, intracellular free calcium ([Ca2+]i), morphologic changes of cell surface and the expression of nm23-H1, p53, ras, c-myc, c-erbB2, bcl-2 genes and PCNA. The correlation between different biologic features and the metastatic potential of the two strains was analyzed. We found: 1) Both strains had the karyotypic abnormality of -13, -14, -15, +20, +21 with seven same marker chromosomes. Only strain D had the karyotypic abnormality of +7, -17, -18, +X, 7p+; 2) [Ca2+]i of the strain C (984.7 +/- 573.8) and D (517.6 +/- 216.6) was significantly different (p < 0.05). The amplitude of intracellular calcium oscillations of strain C was lower than the one of strain D; 3) strain C had more villous-like protrusions on the cell surface, whereas strain D had more bubble-like protrusions; 4) The expression of nm23-H1 and p53 protein of strain C was all higher than that of strain D. The expression of PCNA of strain C was lower than strain D; 5) nm23-H1 mRNA levels of strain C was lower than that of strain D. We consider that the karyotype of chromosomes, intracellular free calcium, the structure of cell membrane and the expression of nm23-H1 gene, p53 gene, PCNA could be closely related to the metastatic potential of human giant-cell lung carcinoma. They could be used as the sign for judging whether the tumor will metastasize in clinical practice as well as in judging the prognoses of patients.
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PMID:Study on the metastatic mechanisms of human giant-cell lung carcinoma comparison between the strains C and D. 1021 98

Both p53 and bcl-2 genes are involved in regulating cell death. Reports, however, concerning the relationship between p53 and bcl-2 expression are contradictory. Large-cell neuroendocrine carcinoma (LCNEC) of the lung is a newly recognized clinicopathologic entity. p53 mutation and bcl-2 overexpression are frequent in small-cell lung carcinoma (SCLC), and we observed a close correlation between bcl-2 expression and cellular neuroendocrine (NE) differentiation in non-SCLC, so we speculated that LCNEC, an NE tumor closely related to SCLC, would exhibit high incidence of both p53 alteration and bcl-2 expression. Immunohistochemical expression of p53 and bcl-2 was evaluated on consecutive sections of 26 LCNECs, including 4 combined LCNECs. p53 accumulation and diffuse bcl-2 staining were observed in 18 (69.2%) of 26 and 24 (92.3%) of 26 LCNECs, respectively, but their immunoreactivities showed no fixed distribution relevance on consecutive sections in individual tumors. Statistical analyses yielded no relationship between p53 and bcl-2 expression (P = .47). In all of the four combined LCNECs, p53 was identically either positive or negative in both tumor cell populations with and without NE differentiation. bcl-2 immunoreactivity was observed only for the tumor cells with NE phenotype in three of the four combined LCNECs and was diffuse among the NE tumor cells but geographic in distribution among the non-NE tumor cells of the remaining one combined LCNEC. Thus, our present findings suggest that p53 and bcl-2 are expressed independently and might have distinct expression significance in LCNECs. A high incidence of p53 expression in LCNECs and equal p53 expression profiles in NE and non-NE tumor cell populations of combined LCNECs suggest that p53 alteration is primarily involved in the tumorigenesis of LCNEC. On the other hand, frequent bcl-2 expression in pure LCNECs and selective bcl-2 expression in tumor cells with NE phenotype in combined LCNECs are suggestive of a role for bcl-2 in regulating cellular NE differentiation.
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PMID:The significance of frequent and independent p53 and bcl-2 expression in large-cell neuroendocrine carcinomas of the lung. 1022

The therapeutic opioid methadone, used to treat cancer pain and opioid addiction, is also a potent inducer of apoptosis in human lung cancer cells, thereby inhibiting their growth. However, in contrast to its central nervous system (CNS) actions, this effect appears to be mediated through a non-opioid mechanism involving bombesin, an autocrine growth-stimulatory factor that plays a central role in the early events of pulmonary carcinogenesis. Exposure of 'variant' small cell lung carcinoma (SCLC) and non-SCLC cells, which secrete low concentrations (< 0.01 pmol/mg protein) of bombesin, to nanomolar concentrations of methadone resulted in increased levels of mitogen-activated protein (MAP) kinase phosphatases and inactivation of MAP kinase, suppression of the bcl-2 protein, and induction of apoptosis. These effects of methadone were reversed by the addition of bombesin to the culture medium, at concentrations of < 1 microM, and 'classic' SCLC cells, which secrete high concentrations of bioactive bombesin (> 6 pmol/mg protein), were found not to respond to methadone. Thus, methadone's effectiveness is dependent upon the concentration of bioactive bombesin secreted by lung cancer cells. Methadone treatment suggests a novel therapeutic approach for patients presenting 'variant' SCLC and non-SCLC morphologies, since they respond less to conventional therapy.
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PMID:Effects of bombesin on methadone-induced apoptosis of human lung cancer cells. 1035 47

An in vitro model that might be relevant to cancer cell chemoresistance in vivo was generated by exposing the human lung carcinoma clonal cell line DLKP-SQ to 10 sequential pulses of pharmacologically attainable doses of doxorubicin. The resistant variant, DLKP-SQ/10p, was found to be cross-resistant to doxorubicin (10x), vincristine (43x), etoposide (3x), sodium arsenate (3x), paclitaxel (38x) [which could imply overexpression of P-glycoprotein (P-gp) and possibly increased multidrug resistance-associated protein activity] and 5-fluorouracil (4x), but slightly sensitized to carboplatin. Analysis of mRNA levels in the resistant variant revealed overexpression of mdr1 mRNA without significant alteration in mrp, Topo. IIalpha, GSTpi, dhfr or thymidylate synthase mRNA levels. Overexpression of the anti-apoptotic bcl-xL transcript and the pro-apoptotic bax mRNA was also detected but no alterations in bcl-2 or bag-1 mRNA levels were observed. Resistance to a P-gp-associated drug, doxorubicin, could be reversed with P-gp circumventing agents such as cyclosporin A and verapamil, but these substances had no effect on resistance to 5-fluorouracil. Overexpression of the pro-apoptotic bcl-xS gene in the DLKP-SQ/10p line partially reversed resistance not only to P-gp-associated drugs but also to 5-fluorouracil, indicating that the ratio of bcl family members may be important in determining sensitivity to chemotherapeutic drug-induced apoptosis.
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PMID:Altered expression of mRNAs for apoptosis-modulating proteins in a low level multidrug resistant variant of a human lung carcinoma cell line that also expresses mdr1 mRNA. 1039 54

Tumors, such as the murine Lewis lung carcinoma (LLC), produce granulocyte-macrophage colony-stimulating factor (GM-CSF), which increases the proportion of CD34(+) hematopoietic progenitor cells in the bone marrow and in the periphery. This increase in peripheral CD34(+) cells had been attributed to the growth-promoting and mobilizing effects of the tumor-derived GM-CSF. However, the possibility that the CD34(+) cells of tumor bearers might have enhanced survival abilities had not been considered. The present studies showed a significant baseline level of apoptotic cells in short-term (5-day) cultures of normal CD34(+) cells containing GM-CSF plus stem cell factor (SCF), and a markedly greater level of apoptosis in cytokine-deficient cultures. In contrast, CD34(+) cells from tumor bearers did not undergo such levels of apoptosis, even in the absence of cytokines. This resistance to apoptosis could be conferred to normal CD34(+) cells by culture with LLC-conditioned medium. Studies to elucidate possible mechanisms for the resistance to apoptosis by tumor-exposed CD34(+) cells showed increased levels of the pro-life gene product bcl-2. Finally, the resistance of tumor-exposed CD34(+) cells to ligation of the Fas receptor, a known apoptotic trigger in hematopoietic cells, was compared with that of control CD34(+) cultures. Whereas approximately half of the normal CD34(+) cells underwent apoptosis in response to Fas ligation, the tumor-exposed CD34(+) cells resisted apoptosis, even though their surface Fas expression was greater than that of normal CD34(+) cells. Thus, our results show that the increased level of CD34(+) cells in tumor bearers is due not only to an increased growth and mobilization of CD34(+) cells as previously thought, but also may be due to an increased resistance to apoptosis that is conferred by tumor-derived products and is associated with increased expression of bcl-2.
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PMID:Increased resistance to apoptosis by bone marrow CD34(+)progenitor cells from tumor-bearing mice. 1040 79


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