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 cells

We have observed weak expression of calponin hl, which stabilizes the actin filament system, in blood vessels within human malignant tumors. This obse rvation suggested that because of a deficiency in stabilization by calponin hl, the structure of blood vessels in malignant tumors is fragile compared with blood vessels in normal tissues. We therefore generated calponin h1-d eficient (CN-/-) mice to examine the effect of calponin hl on the integrity of the barrier system in blood vessels against cancer metastasis. The CN-/ - mice exhibited morphological fragility of the tissues, including the uter us and blood vessels. In particular, we frequently observed bleeding into t he surrounding tissue from blood vessels of the ocular fundus in CN-/- mice . In addition, mesothelial cells, which usually express calponin hl in norm al (CN+/+) mice, were retracted in the CN-/- mice. When fluorescein was inj ected Lv. into mice, the CN-/- mice exhibited a greater and more rapid leak age of fluorescein from the blood vessels of the ocular fundus compared wit h the CN+/+ mice. In the CN-/- mice receiving i.v. inoculations of B16 mela noma cells, significantly more metastatic nodules were formed in the lung t han in the CN+/+ mice. When B16 melanoma cells were injected i.p., the seve rity of peritonitis carcino-matosa was greater in CN-/- than in CN+/+ mice. These results indicate that calponin hl plays an important role in the reg ulation 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 serv e as sensitive and useful host models to investigate cancer metastasis.