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It is well established that human tumors overproduce plasmin a serine protease that is known to promote angiogenesis, tumor growth and metastasis. However, the mechanism by which endothelial or tumor cells regulate the proteolytic activity of plasmin is not well understood. Cell surface receptors regulate activation of plasminogen to plasmin and its proteolytic activity. Annexin II is one of the well studied receptors for plasminogen and tPA, which binds to plasminogen and converts it to plasmin. Plasmin is a highly reactive enzyme which is physiologically involved in fibrinolysis. Since the proteolytic activity of plasmin is very tightly regulated, uncontrolled production of plasmin can degrade extracellular matrix (ECM) and basement membrane (BM) of the surrounding blood vessels. Thus plasmin plays an important role in neoangiogenesis and cancer invasion and metastasis. Therefore, the receptor which regulates plasmin generation may be an attractive target for the development of anti-cancer/anti-metastatic agents. Angiostatin (AS), internal fragment of plasminogen, has been reported to inhibit human tumor growth and metastasis. We have shown that AS binds to endothelial/cancer cell surface annexin II with high affinity and interferes with plasmin generation suggesting that the role of plasmin/plasminogen system may be more complex than we previously thought. In this review we provide a comprehensive analysis of the literature in context of the role of annexin II in angiogenesis, tumor progression and metastasis. Compelling evidence from the literature and our own findings suggest that annexin II may be a potential target for the development of effective therapeutic strategies for the treatment of cancer and its induced metastasis.

Ultraviolet B (UVB) irradiation potently induces cytokines in the skin, including interleukin-1α (IL-1α) and tumor necrosis factor-α (TNF-α). The mechanism for TNF-α induction in UVB-irradiated keratinocytes is not clear. In the current study, we explored the effects of UVB and cytokines, alone or in combination in human keratinocytes. Keratinocytes were sham- or UVB-irradiated with 30 mJ/cm2, and then incubated in the absence or presence of IFN-α2b, TNF-α or IL-1α. UVB and IL-1α treatment synergistically enhanced TNF-α secretion and mRNA levels in human keratinocytes, similar to the findings reported previously in human fibroblasts. Exogenous recombinant TNF-α up-regulates its own mRNA level. However, addition of IFN-α2b did not show any additive effect on TNF-α mRNA induction. To understand the regulation of TNF-α mRNA by UVB, with or without IL-1α, we examined the transcription rate and half-life of TNF-α mRNA. Treatment of keratinocytes with IL-1α or UVB alone increased TNF-α gene transcription 4–5-fold over sham treatment, and TNF-α gene transcription increased 11-fold in cells treated with UVB plus IL-1α over sham. UVB with IL-1α did not enhance the half-life of TNF-α mRNA over that seen with UVB alone. In conclusion, TNF-α expression in primary keratinocytes is up-regulated transcriptionally by UVB and IL-1α.