Sir,
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 (0.1–0.5 mg ml−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.
Change history
29 March 2012
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Daveau M, Rouet P, Scotte M, Faye L, Hiron M, Lebreton JP, Salier JP (1993) Human inter-alpha-inhibitor family in inflammation: simultaneous synthesis of positive and negative acute-phase proteins. Biochem J 292 (Part 2): 485–492
Garantziotis S, Hollingsworth JW, Ghanayem RB, Timberlake S, Zhuo L, Kimata K, Schwartz DA (2007) Inter-alpha-trypsin inhibitor attenuates complement activation and complement-induced lung injury. J Immunol 179: 4187–4192
Hamm A, Veeck J, Bektas N, Wild PJ, Hartmann A, Heindrichs U, Kristiansen G, Werbowetski-Ogilvie T, Del Maestro R, Knuechel R, Dahl E (2008) Frequent expression loss of inter-alpha-trypsin inhibitor heavy chain (ITIH) genes in multiple human solid tumors: a systematic expression analysis. BMC Cancer 8: 25
Michlmayr A, Bachleitner-Hofmann T, Baumann S, Marchetti-Deschmann M, Rech-Weichselbraun I, Burghuber C, Pluschnig U, Bartsch R, Graf A, Greil R, Allmaier G, Steger G, Gnant M, Bergmann M, Oehler R (2010) Modulation of plasma complement by the initial dose of epirubicin/docetaxel therapy in breast cancer its predictive value. Br J Cancer 103: 1201–1208
Opal SM, Lim YP, Siryaporn E, Moldawer LL, Pribble JP, Palardy JE, Souza S (2007) Longitudinal studies of inter-alpha inhibitor proteins in severely septic patients: a potential clinical marker and mediator of severe sepsis. Crit Care Med 35: 387–392
Werbowetski-Ogilvie TE, Agar NY, Waldkircher de Oliveira RM, Faury D, Antel JP, Jabado N, Del Maestro RF (2006) Isolation of a natural inhibitor of human malignant glial cell invasion: inter alpha-trypsin inhibitor heavy chain 2. Cancer Res 66: 1464–1472
Yagyu T, Kobayashi H, Matsuzaki H, Wakahara K, Kondo T, Kurita N, Sekino H, Inagaki K (2006) Enhanced spontaneous metastasis in bikunin-deficient mice. Int J Cancer 118: 2322–2328
Zhuo L, Hascall VC, Kimata K (2004) Inter-alpha-trypsin inhibitor, a covalent protein-glycosaminoglycan-protein complex. J Biol Chem 279: 38079–38082
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Garantziotis, S. Modulation of plasma complement by the initial dose of epirubicin/docetaxel therapy in breast cancer and its predictive value. Br J Cancer 104, 542 (2011). https://doi.org/10.1038/sj.bjc.6606068
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bjc.6606068