Identification of molecules responsible for invasion-independent pathway of blood-borne metastasis.

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Establishment of mouse metastatic model and identification of metastasisl-related genes : We separated sublines and clonal cell lines different in metastatic potential ; 66C8 (a non-metastatic clone), 66HM and Lu10 (highly metastatic sublines to general organs), etc from a mouse mammary tumor cell line (MCH66P) metastasizing via an invasion-independent pathway. A comparative study using these cells demonstrated that invasion-independent metastasis is related to high angiogenesis activity, especially sinusoidal development of tumor vasculature. To identify candidate genes responsible for this type of metastasis we performed differential screening using suppressive subtractive hybridization (SSH) method. Pleiotrophin, Secretory leukocyte protease inhibitor (SLPD), S3B, etc. were cloned as differentially expressed genes in higher metastatic cells among the sublines and clonal cell lines. We next transfected the candidate genes in 66C8 cells. Of five genes SLPI promoted spontaneous metastatic potential to the lung and induced sinusoidal development of tumor vessels as an index of invasion-independent metastasis.Application of the invasion-independent metastasis model to human cancers : Histological examination using archival specimens of 10 common types of human cancers demonstrated that an invasion-independent metastatic pathway is possible in a wide variety of human cancers, especially in most cases of renal cell carcinomas, hepatocellular carcinomas and follicular thyroid carcinomas. Immunohistochemical study showed that SLPI, which promoted invasion-independent metastasis in the mouse model, was also highly expressed in real cell carcinoma.Further studies based on these results may enable us to identify novel genes related to cancer metastasis and may present new therapeutic strategies for the amelioration of human cancers.