Fragmenting the platelet to reduce metastasis

In this issue of Blood, Zhang et al describe an antiplatelet reagent attacking metastasis, the most deadly aspect of cancer.¹  Their experiments outline an early-stage preclinical approach providing proof-of-principle for antiplatelet strategies that may ultimately lead to an improved prognosis for the cancer patient.

The platelet's relevance beyond normal hemostasis and thrombosis continues to grow, due in part to a wealth of reagents and animals models.²  The supportive role of platelets in various aspects of cancer provides the background for studies targeting the platelet.³  Specifically, Zhang et al target the β3 subunit of the platelet's fibrinogen receptor, αIIbβ3, with a humanized single-chain antibody (scFv). The generation and antiplatelet properties of the scFv have been previously reported but these investigators have expanded their characterization to include antimetastatic properties.

Rather than a simple inhibition of αIIbβ3 function, the intriguing property of this scFv is its ability to induce oxidative platelet fragmentation preferentially for an activated platelet (see figure). The scFv recognizes a linear sequence within the extracellular portion of both the mouse and human β3 subunits. The success of the reagent in reducing metastasis is probably based on platelet–tumor cell interactions where the platelet shields the tumor cell in the circulation from the immune system and/or provides a fibrin-rich mesh to support extravasation from the bloodstream.^4,5  One of the more interesting results for the scFv is its minimal side effects in causing thrombocytopenia or increasing the bleeding risk in animal models. Supportive experiments confirm the scFv effects are restricted to antiplatelet properties and not via anti-β3 effects on other cell types, such as endothelial cells.

The possibility for this type of antiplatelet targeting is very intriguing both in the realm of cancer therapy and for all platelet influenced pathologies. The results suggest the scFv is only eliciting its antiplatelet activity when activated platelets are bound to tumor cells. Balancing the normally needed platelet properties in hemostasis and inhibiting platelet function in other pathologic settings has remained one of the biggest challenges in the development of antiplatelet therapies. While measurement of mouse bleeding is less sophisticated than assessing human bleeding, the possibility of maintaining normal hemostasis while targeting the activated platelet would be met with great anticipation.

Somewhat unexpected, the scFv appears to have no effect on angiogenesis. While platelets are known to store and release both pro- and anti-angiogenic proteins the inability of the scFv to influence angiogenesis is most likely related to the state of the platelet targeted by the scFv. Indeed, the fragmentation elicited by the scFv may still release stored proteins that support the platelet's relevance in angiogenic pathways, but more work on this topic is needed to completely understand.

If these results are to translate to clinical trials the in vivo mouse models used by Zhang et al must reflect the human cancer situation. The models used are common approaches for studying metastasis but neither may exactly mimic the situation occurring in human disease. In experimental metastasis a large bolus of tumor cells is injected into the venous circulation and the majority of cells are quickly lodged during transport to their first capillary bed in the pulmonary circulation. Thus, experimental metastasis produces a dramatic number of tumor nodules in the lung. Secondly, the spontaneous model represents a large primary subcutaneous tumor where some cells do leave the site to also find a capillary bed for extravasation in lung tissue. How predictive these models are to the complex events surrounding human metastatic disease is still an open question.

Moving forward there still exist challenges. First is the relatively short window within which the anti-β3 scFv is effective. The injection of the scFv 4 hours before, or after, the addition of tumor cells to the vasculature was effective at reducing metastasis. Administration of the scFv 12 hours before, or after, tumor cell addition was not effective. Are there situations where a short time frame of administration could still be advantageous? Purely speculative at this point, but perhaps during surgical removal of a primary tumor the scFv could be a temporary second line of defense to reduce the likelihood of viable tumor cells traveling through the bloodstream. There may be methods to improve the half-life of the anti-β3 scFv in the bloodstream and this would be obvious improvement now that the exciting basic proof-of-principle data exist.