Osteopontin as a Biomarker for Ovarian Cancer

To the Editor: Dr Kim and colleagues¹ found elevated serum osteopontin levels in patients with ovarian carcinoma. While the authors' approach has high sensitivity, the nonspecific nature of osteopontin expression in many diseases limits the potential clinical application of serum osteopontin as a unique biomarker for ovarian cancer.

Test specificity is central to any biomarker or screening program. Osteopontin may be expressed in many inflammatory and noninflammatory diseases including cancers of varied tissue origin.^{2 - 3} Although a variety of cell types express osteopontin, macrophages are a major source.² Even in carcinoma, there is evidence that infiltrating macrophages rather than tumor cells are the principal source of osteopontin.³ Prior investigations have shown very high levels of osteopontin in hemodialysis patients with arterial atherosclerosis and in patients with gram-negative sepsis.⁴ These studies suggest that assays of total serum osteopontin alone will lack sufficient specificity to be a clinically applicable cancer biomarker.

In contrast to total osteopontin, there is evidence that different isoforms of osteopontin may have distinct functions, and thus analysis of these isoforms may be more helpful in cancer screening. At least 3 transcriptional variants of osteopontin have been described and osteopontin is extensively posttranslationally modified.² Indeed, phosphorylated and dephosphorylated forms of osteopontin have distinct functions in inflammatory diseases.² Furthermore, in experimental models of squamous cell carcinoma, tumor-derived osteopontin augments tumor growth, whereas macrophage-derived osteopontin inhibits growth.⁵ The fact that tumor-derived and macrophage-derived osteopontin have apparently opposite effects on tumor growth suggests that further studies may define tumor-specific isoforms of osteopontin.

Based on the nonspecific nature of osteopontin expression in many distinct diseases, we urge caution in interpreting the role of osteopontin as a potential cancer biomarker. This is particularly relevant as osteopontin is expressed in diseases with subclinical phases such as sarcoidosis and atherosclerosis.² These limitations could be overcome by the identification of tissue-specific osteopontin isoforms and further studies that define their specificity in patients with nonmalignant inflammatory disease.