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Structural Fragility of Blood Vessels and Peritoneum in Calponin h1-deficient Mice, Resulting in an Increase in Hematogenous Metastasis and Peritoneal Dissemination of Malignant Tumor Cells¹

Department of Molecular Oncology and Angiology, Research Center on Aging and Adaptation [S. T., M. T., S. H.], Department of Pathology [T. E., H. S.], and Department of Ophthalmology [H. S., N. Y.], Shinshu University School of Medicine, Matsumoto 390-8621; Department of Medicine, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537 [K. T.]; The Graduate School of Pharmaceutical Science, Osaka University, SORST, Japan Science and Technology Corporation, Osaka 537 [K. T.] Japan; Institute of Medical Science, University of Tokyo, Tokyo 108-8639 [M. K.], Japan

We have observed weak expression of calponin h1, which stabilizes the actin filament system, in blood vessels within human malignant tumors. This observation suggested that because of a deficiency in stabilization by calponin h1, the structure of blood vessels in malignant tumors is fragile compared with blood vessels in normal tissues. We therefore generated calponin h1-deficient (CN^-/-) mice to examine the effect of calponin h1 on the integrity of the barrier system in blood vessels against cancer metastasis. The CN^-/- mice exhibited morphological fragility of the tissues, including the uterus and blood vessels. In particular, we frequently observed bleeding into the surrounding tissue from blood vessels of the ocular fundus in CN^-/- mice. In addition, mesothelial cells, which usually express calponin h1 in normal (CN^+/+) mice, were retracted in the CN^-/- mice. When fluorescein was injected i.v. into mice, the CN^-/- mice exhibited a greater and more rapid leakage of fluorescein from the blood vessels of the ocular fundus compared with the CN^+/+ mice. In the CN^-/- mice receiving i.v. inoculations of B16 melanoma cells, significantly more metastatic nodules were formed in the lung than in the CN^+/+ mice. When B16 melanoma cells were injected i.p., the severity of peritonitis carcinomatosa was greater in CN^-/- than in CN^+/+ mice. These results indicate that calponin h1 plays an important role in the regulation of the integrity of the blood vessels and peritoneum, which in turn is an important factor influencing the frequency of cancer metastasis. The CN^-/- mice, which exhibit fragile blood vessels and peritoneum, could serve as sensitive and useful host models to investigate cancer metastasis.

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