To investigate chemopreventive effect of liposomal b b-sitosterol on tumor metastasis, we prepared liposomal b b-sitosterol composed of egg yolk phosphatidylcholine for oral delivery. Although orally administered b b-sitosterol (4 m mmol as b b-sitosterol/mouse) was not absorbed into plasma, the amount of immune response cytokines such as IL-12 and IL-18 was increased in the small intestine after the liposome intake. Moreover, after daily oral administration of the liposome for 7 d, natural killer (NK) cell activity in the mice was increased, suggesting that the immune surveillance activity of mice was enhanced by the liposomal b b-sitosterol intake. Thus, we examined metastatic potential of B16BL6 melanoma cells, which were intravenously injected into mice after sequential administration of liposomal b b-sitosterol for 7 d. The number of metastatic colonies in the lungs was significantly less than that of control group two weeks after the injections of the cells. These results suggest that daily liposomal b b-sitosterol intake prevents tumor metastasis may be due to enhancement of gut immune surveillance systems.
Tumor metastasis is a key step in the development of a tumor and becomes a critical trigger for the death of a patient. Hematogenous metastasis is established by a series of steps, which begin with the dissociation from primary sites and culminate with the formation of metastatic colonization.1) This process is greatly dependent on surrounding host factors such as host resistance to cancerous cells. 2,3) In a previous study, we demonstrated that the early accumulation of metastatic tumor cells in a target organ after intravenous injection of the cells and following tumor metastasis were enhanced by reduction of the host immune surveillance potential, 4,5) suggesting that avoidance of the surveillance associated with immune cells, such as natural killer (NK) cells, was a critical step for the completion of an experimental tumor metastasis.The senescence-accelerated mice prone (SAMP) strain has been established as a mouse model for aging research 6) and exhibits a more accelerated senescence process than normal mice. 7,8) By using this model, we found that the immune surveillance potential of 8-month-old aged SAMP10 mice was lower than that of 2-month-old young mice, and that the experimental lung metastasis was significantly induced in aged mice. These data suggest that the aging process produces an environment susceptible to metastatic tumor cells in the bloodstream to complete metastasis, and that such an environment is produced with age due to the reduced immune surveillance potential. 9)Green tea (GT)-catechins are functional polyphenols, and are known to have various actions, such as antibiotic, antiinflammatory, antioxidative, and anti-cancer effects. It is anticipated they will become useful as a functional food that promotes human health and longevity. Although animal studies have shown that GT-catechin treatment suppressed tumorigenesis, tumor growth, and tumor angiogenesis, 10,11) the crucial mechanism of the action of GT-catechin against cancer has not been fully elucidated. Our previous study demonstrated that (Ϫ)-epigallocatechin gallate (EGCG, a major component of GT-catechins) suppressed tumor angiogenesis through the inhibition of membrane type-1 matrix metalloproteinase (MT-1MMP) activity and subsequent induction of dormancy of solid tumor growth. 12,13) Tachibana et al. also reported that 67-kDa laminin receptors are a receptor for EGCG and that EGCG treatment inhibited the receptor-mediated signaling pathway and subsequent tumor cell growth.14,15) Several reports have described various such approaches to treat and prevent cancer using GT-catechins. In the present study, we hypothesized that GT-catechin intake modulates the immune surveillance potential in aged mice, and enhances the susceptibility to experimental tumor metastasis. To prove this, we exposed SAMP10 mice to GT-catechin in their drinking water for an extended period of time (aged/catechin mice) and examined their NK activity as an indicator of immune surveillance potential. We then also examined the accumulation of K1735M2 melanoma...
Since most cancer incidence is related to the accumulation of gene mutations, 1) the majority of cancer patients are of the elderly generation and cancer is the highest cause of death for them. These generations are often referred to as "cancer age" and cancer seems to be one of the age-related diseases. 2)On the other hand, cancer development is known to depend on the surrounding host environment.3) For example, tumor cell growth in the young is faster than that in the aged due to alterations in host factors. 4,5) Thus, it is possible that the aging process also affects cancer development by alteration of the host environment. 6,7) Cancer metastasis is often the critical trigger for the death of a patient. It begins to dissociate from primary sites and culminates with the formation of metastatic colonization. 8)These processes are very sensitive to the surrounding host factors such as the host resistance to cancerous cells. In a previous study, we suggested that it is a critical step for tumor cells in experimental tumor metastasis to avoid the host immune surveillance associated with immune cells such as natural killer (NK) cells and macrophages.9) Because the early accumulation of metastatic tumor cells in the target organ well reflected the eventual tumor metastasis, it was demonstrated that the immune system functioned to remove the tumor cells from the bloodstream and the target site in the early stage of tumor metastasis.10) From these observations, we speculated that the experimental metastatic potential would be altered with age due to the age-dependent alteration of host resistance to the metastatic tumor cells. In the present study, we investigated the alteration of experimental tumor metastasis between young and aged mice using senescenceaccelerated mice (SAM).The SAM prone (SAMP) strain was originally established as a mouse model for aging research 11,12) and shows a more accelerated senescence process than normal mouse, such as a shorter lifespan, a compromised immune system, and development of several geriatric disorders which are frequently observed in aged humans.12,13) Thus, we theorized that aged SAMP was a more appropriate model for cancer research than the young healthy mice usually used in experimental models. We used one of the SAMP strains, SAMP10, which showed several geriatric disorders such as brain atrophy. 14,15) In the present study, we investigated the alteration of tumor metastatic potential with age in those mice: 2-month-old SAMP10 was used as the "young" model and an 8-monthold as the "aged". Alteration of the NK activity with age was first examined, because NK cells are well known to work on the first line of defense against mutant cells such as cancerous cells. 16,17) Next, we investigated the early accumulation of highly lung-metastatic K1735M2 melanoma cells in the target organ using positron emission tomography (PET) and the 5-[ MATERIALS AND METHODSAnimals Senescence-accelerated mouse prone 10 (SAMP10) was purchased from Japan SLC Inc. (Shizuoka, Japan). Two-month-old SA...
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