Enhanced Experimental Tumor Metastasis with Age in Senescence-Accelerated Mouse

Abstract

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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“…It has been demonstrated that single SASP factors regulate key processes that facilitate tumor progression and metastasis including proliferation, senescence, angiogenesis, epithelial mesenchymal transition and immune evasion (2,53,55).…”

Preventive Effect of Green Tea Catechins on Experimental Tumor Metastasis in Senescence-Accelerated Mice

“…18,19) Our previous study demonstrated that the aging process caused the enhancement of susceptibility to experimental tumor metastasis in senescence-accelerated mice and the reason why it occurs was suggested to be due to a reduction in immune surveillance potential against metastatic tumor cells with age. 9) These findings suggest that the maintenance of a healthy internal environment in aged animals would improve the age-related weakening of the protective effect against experimental metastasis.…”

“…This result confirmed those of our previous study and demonstrated that tumor metastasis was accelerated in an age-dependent manner. 9) In an attempt to inhibit tumor metastasis in old age, we exposed aged SAMP10 mice to GTcatechin water (0.02% Polyphenon70S) for an extended period of time. When the daily intake volume of GT-catechin water was measured, the volume was about 10 ml/d/mouse and was almost the same as for the group given normal water.…”

“…They began to show several senescence symptoms such as brain atrophy and dehairing from about 6 months-old. Since their immune surveillance potential was adequately reduced at 8 months-old, 9) we used 8-month-old or older SAMP10 mice as an appropriate model for the cancer prone age (aged SAMP10 mice). In another group of aged mice (aged/catechin SAMP10 mice), water containing 0.02% (w/v) GT-catechins (Polyphenon70S, Mitsui Norin Co., Ltd., Tokyo) was given ad libitum beginning Cells Highly lung-metastatic, murine K1735M2 melanoma cells were kindly provided by Dr. Jun Yokota of the National Cancer Center (Tokyo, Japan).…”

“…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.…”