E-30. The hallmarks of lung cancer

Abstract

In a seminal article, Hanahan and Weinberg identified six hallmarks into which the vast majority of cancer related genomic and phenotypic changes may be classified [l]. In this presentation we will discuss how the genomic changes associated with lung cancers can be fitted into these hallmarks. Data are rapidly accumulating from a host of new technologies, both genomics and proteomics, and the use of suitable control tissues such as the establishment of immortalized but non malignant bronchial epithelial cell cultures will greatly assist our interpretation. Small cell (SCLC) and non-small cell (NSCLC) lung cancers share many common features as well as have unique molecular characteristics. Obviously the more than 100 changes described to date cannot be discussed in a few minutes. We will highlight some of the important recent discoveries as they relate to previously or recently identified genes, and discuss some of the potential clinical or therapeutic aspects of these findings. Some changes impact on multiple hallmarks, and alterations in one hallmark may affect others. For instance mutations of the ~53 gene impact on apoptosis, insensitivity to anti-growth signals and possibly other hallmarks. In addition, p53 mutations and several of the other genetic changes, individually or in aggregate lead to genomic instability which predisposes to further alterations. In addition, there is considerable crosstalk between components of the hallmarks. The hallmarks are as follows: Self sufficiency in growth signals. Tumor cells acquire the capacity to generate their own cell cycle signals. This is largely due to effects of dominant oncogenes, which include up regulation of HER2/neu, epidermal growth factor and myc While ras mutations are present in about 30% of adenocarcinomas, disruption of its signaling pathway is probably present in most or all lung cancers. Ras mutations are absent in SCLC. One reason may be because of the frequent methylation and silencing of the RASSFIA gene which binds ras in a GTP dependent manner, but which also functions as a transcription factor and induces apoptosis. While COX2 is up regulated in NSCLC, paradoxically, it is specifically down regulated in SCLC, raising the specter that COX2 inhibitors may prevent one form of lung cancer while stimulating another! Up regulation of the JAWSTAT pathway is another recently described phenomenon and occurs via multiple mechanisms including autocrine cytokine production as well as by loss of natural inhibitory proteins.