Antimetastatic Effect by Targeting CTC Cluster—Response

We appreciate two commentaries from Dr. Alonso and Dr. Soria's groups regarding our recent publication on “highly metastatic property of clustered circulating tumor cells (CTC).” In our research, we suggested the breakdown of CTC cluster slows metastasis pace with preclinical experiments; urokinase plasminogen activator (uPA) utilized to dissociate the CTC cluster showed no effect on primary tumor growth, but the number of metastasized nodules was reduced, expanding survival rate of the animals (1).

Two different animal models, B16F10 melanoma cells in C57BL/6 and 4T1 mammary carcinoma in balb/c, were tested and showed a similarly rapid animal death in 6 to 7 weeks after subcutaneous inoculation of cancer cells. In addition, the subcutaneously transplanted cancer cells have a preexisting metastatic ability, whereas in spontaneous tumor, some cells acquire the invasion ability. Hence, the disease animal models may undergo a physiologically different disease progress and tumor microenvironment from those of human patients who generally suffer from various systemic physical changes due to long disease history. Thus, we agree with the concerns of Dr. Soria and colleagues that the potential of uPA as risk factor may not be ruled out. The other reports consistently support a cancer-promoting role of uPA and chemical intervention on uPA is expected as cancer therapeutic method (2, 3). In our experimental condition, it is likely that CTC cluster–dissociating potential of uPA was dominant over its disease-driving effect due to extremely rapid metastasis. Clinical application of uPA requires additional careful study.

Recently, Mego and colleagues reported that uPA-related genes were expressed in epithelial CTC, but not in epithelial–mesenchymal transition CTC, which mainly stands for early metastasis. Interestingly, in primary tumor, the urokinase expression was not associated with the presence of CTC in peripheral blood (4). These data suggest that other pathways than uPA system may regulate the emergence of CTC. The letter from Dr. Alonso and colleagues reminds us of the metastasis-promoting role of the fibrolysis inhibitor and also supports a particular treatment condition, such as perioperative stage that may be helpful for antimetastasis of fibrolytic agents. Thus, a CTC cluster–dissociating and antimetastatic effect of fibrolytic agent can still be considered at a limited condition, compatible with metastasis-stimulating potential of urokinase.

We appreciate the comments and interest in our publication as they provide further guidance. We plan to determine factors that influence uPA treatment and how microenvironment controls the interaction between uPA and CTCs in our subsequent studies.

See the original Letter to the Editor, p. 4908