Dickkopf-1 (DKK1) is a secreted Wnt/β-catenin pathway antagonist involved in embryogenesis. It was first described 25 years ago for its function in head induction and limb morphogenesis. Since then, this protein has been widely studied in the context of active Wnt/β-catenin signalling during cellular differentiation and development. Dysregulation of DKK1 has been associated with bone pathologies and has now emerged as a potential biomarker of cancer progression and prognosis for several types of malignancies. Reducing the amount of circulating DKK1 may reveal a simple and efficient strategy to limit or reverse cancer growth. This review will provide an overview of the role of Dickkopf-1 in cancer and explore its potential use as a biomarker and therapeutic target.

IntroductionDickkopf‐1 (DKK1) is a soluble protein and antagonist of the Wnt/β‐catenin signaling pathway. DKK1 is found elevated in serum from patients affected with various types of cancers and in some instances, it is considered a diagnostic and prognostic biomarker. Elevated serum levels of DKK1 have also been detected in animal models of chronic inflammatory diseases. Previous work from our laboratory has demonstrated upregulation of DKK1 in cells and mouse models of the bone marrow failure (BMF) and cancer‐prone disease Fanconi anemia (FA). The present study aimed to investigate whether DKK1 blood levels in patients are associated with FA or inflammatory responses to acute infections.MethodsPlasma samples were collected from 58 children admitted to the Centre Mère‐Enfant Soleil du Centre Hospitalier de Québec‐Université Laval with signs of acute infections. Blood plasma specimens were also collected from healthy blood donors at the Héma‐Québec blood donor clinic. Plasmas from patients diagnosed with FA were also included in the study. DKK1 levels in blood plasmas were assessed by standard ELISA.ResultsPatients with acute infections showed dramatically high levels of DKK1 (6072 ± 518 pg/ml) in their blood compared to healthy blood donors (1726 ± 95 pg/ml). No correlations were found between DKK1 levels and C reactive protein (CRP) concentration, platelet numbers, or white blood cell counts. Patients with FA showed higher DKK1 plasma levels (3419 ± 147.5 pg/ml) than healthy blood donors (1726 ± 95 pg/ml) but significantly lower than patients with acute infections.ConclusionThese findings suggest that blood DKK1 is elevated in response to infections and perhaps to inflammatory responses.

Fanconi anemia (FA) is a rare genetic disorder associated with a progressive decline in hematopoietic stem cells leading to bone marrow failure. FA is also characterized by a variety of developmental defects including short stature and skeletal malformations. More than half of children affected with FA have radial-ray abnormalities, and many patients have early onset osteopenia/osteoporosis. Although many Fanconi anemia genes have been identified and a molecular pathway defined, the underlying mechanism leading to bone defects remains elusive. To understand the role of FA genes in skeletal development and bone microarchitecture, we evaluated bone physiology during embryogenesis and in adult FancA- and FancC-deficient mice. We found that both FancA and FancC embryos have abnormal skeletal development shown by skeletal malformations, growth delay, and reduced bone mineralization. FancC adult mice present altered bone morphology and microarchitecture with a significant decrease in cortical bone mineral density in a sex-specific manner. Mechanical testing revealed that male but not female FancC mice show reduced bone strength compared with their wild-type littermates. Ex vivo cultures showed that FancA and FancC bone marrow-derived mesenchymal stem cells ( MSC) have impaired differentiation capabilities together with altered gene expression profiles. Our results suggest that defective bone physiology in FA occurs in utero and possibly results from altered MSC function. These results provide valuable insights into the mechanism involved in FA skeletal defects. © 2018 American Society for Bone and Mineral Research.

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