Increased cell proliferation, which is a hallmark of aggressive
malignant neoplasms, requires a general increase in
protein synthesis and a specific increase in the synthesis of replication-promoting
proteins. Transient increase in the general
protein synthesis rate, as well as preferential translation of specific mRNAs coding for growth promoting
proteins (e.g.
cyclin D1), takes place during normal mitogenic response. A number of extensively studied growth signal transduction pathways (Ras, PI3K, MAPK, mTOR-dependent pathways) activate the function and expression of various components of the translational machinery. In abnormal situations, constitutive activation of signal transduction pathways (e.g. oncogenic activation of Ras or Myc) leads to continuous upregulation of key elements of translational machinery. On the other hand, tumor suppressor genes (p53, pRb) downregulate ribosomal and
tRNA synthesis, and their inactivation results in uncontrolled production of these translational components. During recent years, a significant effort has been dedicated to determining whether expression of translation factors is increased in human
tumors using clinical biopsy specimens. The results of these studies indicate that expression of particular translation
initiation factors is not always increased in human
neoplasms. The pattern of expression is characteristic for a particular
tumor type. For example,
eIF-4E is usually increased in
bronchioloalveolar carcinomas but not in
squamous cell carcinomas of the lung. Interestingly, in certain highly proliferative and aggressive
neoplasms (e.g.
squamous cell carcinoma of the lung,
melanoma), the expression of
eIF-4E is barely detectable. These findings suggest that mechanisms for increasing general
protein synthesis in various
neoplasms differ significantly. Finally, the possibility of qualitative alterations in the translational machinery, rather than a simple increase in the activity of its components, is discussed along with the possibility of targeting those qualitative differences for
tumor therapy.