Different Roles Of Dkk1 In Cancer Metastasis

Wnt signaling is involved in the development and progression of a variety of cancers, and researchers have typically approached Wnt-targeted therapeutics with the aim of suppressing this signaling. Dkk1 is an inhibitor of Wnt signaling, and so this molecule has been thought to be useful with respect to cancer therapy.  But in the paper linked here, it was shown that while Dkk1 inhibits metastasis of lung cancer, it can actually promote metastasis of breast cancer to bone.  This demonstrates that particular therapeutic approaches may need to be specifically targeted to particular cancer types; it also suggests that suppression of signaling is not always the best approach.  There has been some work suggesting boosting cell signaling to abnormally high levels can cause cancer cell death as well; this is a topic worth revisiting in the future.  Abstract:

Metastatic cancer is a systemic disease, and metastasis determinants might elicit completely different effects in various target organs. Here we show that tumour-secreted DKK1 is a serological marker of breast cancer metastasis organotropism and inhibits lung metastasis. DKK1 suppresses PTGS2-induced macrophage and neutrophil recruitment in lung metastases by antagonizing cancer cell non-canonical WNT/PCP-RAC1-JNK signalling. In the lungs, DKK1 also inhibits WNT/Ca2+-CaMKII-NF-κB signalling and suppresses LTBP1-mediated TGF-β secretion of cancer cells. In contrast, DKK1 promotes breast-to-bone metastasis by regulating canonical WNT signalling of osteoblasts. Importantly, targeting canonical WNT may not be beneficial to treatment of metastatic cancer, while combinatory therapy against JNK and TGF-β signalling effectively prevents metastasis to both the lungs and bone. Thus, DKK1 represents a class of Janus-faced molecules with dichotomous roles in organotropic metastasis, and our data provide a rationale for new anti-metastasis approaches.