Signaling pathways responsible for cancer cell invasion as targets for cancer therapy.
Migration of cancer cells is one of the key factors responsible for cancer metastasis. The elucidation of mechanisms responsible for the highly invasive potential of cancer cells can help to identify specific targets for the treatment of cancer patients. Highly invasive cancers are usually characterized by aberrant activity of specific intra- or extracellular molecules such as protein kinases, phosphatases, transcriptional factors, proteolytic enzymes, and others. Protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K) are responsible for the constitutive activity of transcriptional factors NF-kappaB and AP-1 in some of the highly invasive cancers. Furthermore, NF-kappaB and AP-1 control the expression of urokinase-type plasminogen activator (uPA) and its receptor (uPAR), and expression of both uPA and uPAR correlates with invasive cancer cell phenotype and poor prognosis. The inhibition of PKC and PI3K signaling (through NF-kappaB and AP-1) suppressed the secretion of uPA, resulting in the inhibition of motility of highly invasive breast cancer cells. Therefore, inhibition of specific target molecules in common signaling pathway(s) responsible for metastatic spread can have potential clinical relevance. This review will summarize different approaches to targeting distinct signaling molecules involved in cancer invasion and metastasis.
Sliva
Daniel
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Cancer Research Laboratory, Methodist Research Institute, Clarian Health Partners Inc., and Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN 46202, USA. dsliva@clarian.org
D000818:Animals; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000502:physiology; D015398:Signal Transduction; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D016328:NF-kappa B; D011956:Receptors, Cell Surface; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D014568:Urokinase-Type Plasminogen Activator