Neuroendocrine (NE) lung tumors encompass a spectrum from typical and typical carcinoids representing low and intermediate grade tumors respectively and high grade tumors represented by large cell neuroendocrine tumors (LCNEC) [l] and small cell lung carcinoma (SCLC). This may reflect different levels of molecular abnormalities on the scale of genetic lesions giving rise to tumor growth. NE lung tumor spectrum provides a unique opportunity to compare molecular abnormalities between tumors of different grade sharing a common (NE) phenotype. Since tumor growth is the net result of proliferation and cell death, we have studied some of the factors which promote proliferation and decrease cell death (apoptosis). Acceleration of proliferation is the result of both gain of function of proteins encoding growth factors and oncogenes and loss of function of tumor suppressor gene encoded proteins, which normally exerce a negative control on growth signals transmitted by the first category of proteins. Escape from cell death is also partially related to tumor suppressor gene inactivation. We have studied the contribution of some tumor suppressor gene (P53, Rb, Pi 6) inactivation to the malignant potential of NE lung tumors. P53 and Rb, on a common pathway, regulate Gl arrest in case of DNA damage. On a Rb independent pathway, P53 also plays a role in apoptosis. P53 can be viewed as a sensor of genotoxic stress and tumor proliferation of cells with DNA damage. Rb itself is regulated at the level of its phosphorylation, by cyclin-dependent-kinases (CDK), themselves regulated by CDK-Inhibitors (CDK-I). We have studied the two types of Rb inactivation, in NE lung tumors: the direct way which involves the absence of Rb protein expression, and the indirect pathway by which Rb phosphorylation is deregulated: this can be achieved by cyclin Dl overexpression or CDK-I (P16, P1.5) loss of expression. P53 inactivation in NE tumors can be reflected by stabilization of the P53 protein leading to P53 immunohistochemical (IH) detection [2]. P53 stabilization is commonly due to missense mutation, whereas minor types of mutation (20%) are not stabilizing, affect mRNA splicing sites, or create stop codons which interdict protein expression (null P53 phenotype), and generate negative P53 IH phenotype [3] P53 mutation and stabilization are well delineated along the NE lung tumor spectrum. Neither mutations nor P53 positive phenotype (IH) occur in typical carcinoid (TC), although we have observed null phenotype. Atypical carcinoid (AC) despite a low level P53 staining (20%), retain a wi P53 [4]. In contrast, LCNEC and SCLC display a 80% rate of P53 mutation: (from 50-80% using IH, and/or sequence analysis). Thus there is a significant increase in P53 mutation rate between carcinoids (TC + AC) and high grade NE tumors (LCNEC and SCLC) (p = 0.0003) [5]. Rb gene inactivation through absence of Rb protein expression occurs with a significantly increasing rate from TC (20%) to SCLC (80%). We found that absence of transcription was responsible for most of Rb “silencing” (SO%), whereas only 20% was due to mutation within Rb gene sequence [6]. The vast majority of cases which had retaind Rb expression had achieved Rb inactivation through CDK-I (P16) inhibition. Thus, there was an inverse correlation between Rb and P16 expressions in high grade NE lung tumors, SCLC and LCNEC (p = 0.0002). Only TC displayed a constant Rb+, P16+ genophenotype, showing that low grade NE tumors have retained Rb expression and the control of its phosphorylation. LCNEC differ from SCLC by a less drastic Rb loss, compensated by a highest rate of P16-P15 inactivation (very uncommon in NSCLC). Two dominant interacting proteins Bax and Bcl2 regulate the cell susceptibility to death in NE cells, and are under the transcriptional control of P53. There is a striking inverse relationship between bax and bcl2 at the level of individual tumors, and between low grade carcinoids and high grade LCNEC and SCLC. Along the NE lung tumors spectrum, increasing rate and level of bcl2 expression are paralleled by a decreasing rate and level of bax expression. This inverse relation crosses the spectrum at the level of AC. Interestingly, there is a strong relationship between high bax expression, low bcl2 expression and bax:bcl2 ratio more than unit, with prolonged survival in NE (excepted SCLC) across histological groups p < 0.002) [5]. This relation between bax:bcl2 ratio and survival has been confirmed in a large series of AC. Bcl2 increases in post-therapy samples of SCLC following other phenotypical traits of chemoresistant SCLC [7]. The highest levels of bc12 expression and bcl2:bax ratio are associated with P53 mutant immunophenotype (p = 0.02). Whereas P53 mutant phenotype was not related to prognosis in our study, bax and bcl2 balance appears to be the most significant factor for survival prediction in NE lung tumors. This emphasizes the differentiation specificity of bcl2 family proteins which have a weak prognostic value if any in NSCLC. In conclusion, genetic and molecular abnormalities in NE lung tumors confirm the concept of a continuous spectrum of malignancies from TC with no P53 mutation (no smoking habits), a low rate of Rb loss, no CDK-I (P16-P15) inactivation, and a low bcl2:bax ratio, to the high grade LCNEC, SCLC, with high rates of P53 mutation, and Rb loss, and a high bcl2:bax ratio. AC occupy an intermediate grade on the scale of molecular abnormalities. LCNEC is a specific tumor type with severe genetic lesions, differing from SCLC by a lower rate of Rb loss, compensated by a drastic P16-P15 inactivation. The molecular characteristics of NE lung tumors indicate potential therapeutic targets that could ideally “convince” SCLC or LCNEC tumor cells to mimic carcinoid cells. Bax gene transfert, bc12 attenuation, Rb or P16 gene transfer or modulation, might provide therapeutic approaches according to specific molecular pathology status.