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I read with interest the recent paper by Michlmayr et al, 2010, describing the effects of neoadjuvant chemotherapy on serum complement factor expression (Michlmayr et al, 2010). The authors also reported increase in levels of the plasma protein inter-α-trypsin inhibitor (IαI), but they may have failed to appreciate the potential significance of this finding.
IαI is not an acute-phase protein, as the authors report in this paper; in fact IαI plasma concentration declines during acute inflammation, because of consumption and decreased liver expression (Daveau et al, 1993; Opal et al, 2007). Moreover, IαI heavy chain expression is downregulated in cancers, including breast cancer (Hamm et al, 2008). Furthermore, IαI does not simply have hyaluronan-binding properties; it inhibits cancer metastasis (Werbowetski-Ogilvie et al, 2006; Yagyu et al, 2006) and has strong anti-inflammatory properties (Zhuo et al, 2004). In fact, we showed that IαI inhibits complement activation, both through the classical and the alternative pathways (Garantziotis et al, 2007). Thus, the association of increased IαI and complement plasma levels is significant for at least two reasons. First, upregulation of IαI may be a regulatory mechanism inhibiting complement activation. As baseline IαI plasma concentration is substantial (0.1–0.5mgml−1; Zhuo et al, 2004), even a modest relative increase of ~50%, as the authors report, would mean a significant absolute increase. As the observed increase in plasma IαI overrides the expected acute phase decline, powerful induction mechanisms may be assumed. Second, IαI is now in production in the United States and will soon be tested in a clinical trial for its effect in sepsis morbidity and mortality. As complement activation appears to have a role in the response to chemotherapy, factors that affect this activation, such as IαI, may be interesting as therapeutic agents. Furthermore, IαI levels may be predictive of response to treatment as well, as they are in sepsis (Opal et al, 2007).
In conclusion, I believe that IαI–complement interactions are important in the context of cancer progression and treatment, and these interactions should be highlighted in reference to the recently published paper by Michlmayr et al, 2010.