It is generally accepted that histologically similar tumors grow more slowly, with less angiogenesis, in aged mice relative to young mice. We subcutaneously implanted TRAMP-C2 tumor cells, a prostate cancer cell line not previously examined in aging, into syngeneic C57/Bl6 young (4 month) and aged (20 month) mice and compared tumor growth and angiogenesis. Unexpectedly, the prostate tumors grew as fast in aged as in young mice. Angiogenesis in TRAMP-C2 tumors was robust, with no differences between the young and aged mice in the number of vessels, distribution of vessel sizes or features of vessel maturation. Aged mice had lower levels of serum testosterone than the young mice. VEGF levels were similar in the tumors and sera of the young and aged mice. Comparison with B16/F10 melanoma, a cancer cell line that is representative of previous studies in aged mice, showed that B16/F10 tumors grew minimally in the aged mice. In contrast to the B16/F10, TRAMP-C2 tumors had an extracellular matrix with significantly higher levels of MMP2 and MMP9 expression and activity. These unique results demonstrate that tumor progression can be as robust in aged tissues as young tissues. The ability of aged mice to grow large, vascularized prostate tumors is associated with high levels of MMP2/9 activity that may produce a permissive environment for tumor growth and angiogenesis. These data demonstrate that tumor-cell specific features determine the effect of aging on tumor growth and angiogenesis.
"According to Candido et al. (2012), the AR distribution pattern is lobe-specific among the senile rats' accessory sex glands, considering the action of androgens and hormonal imbalance due to this life period. Moreover, the prostate microenvironment of the senile animal could contribute to tumor development , which grows efficiently through consistent angiogenic support (Reed et al., 2007). Studies have suggested that VEGF expression is directly regulated by androgens in both normal tissues and in prostate tumors (Van Moorselaar and Voest, 2002; Delongchamps et al., 2006; Reynolds and Kaprianou, 2006). "
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to evaluate the structural and molecular effects of antiangiogenic therapies and finasteride on the ventral prostate of senile mice.
90 male FVB mice were divided into: Young (18weeks old) and Senile (52weeks old) groups; Finasteride group: Finasteride (20mg/kg); SU5416 group: SU5416 (6mg/kg); TNP-470 group: TNP-470 (15mg/kg,) and SU5416+TNP-470 group: similar to the SU5416 and TNP-470 groups. After 21days, prostate ventral lobes were collected for morphological, immunohistochemical and Western Blotting analyses.
The results demonstrated atrophy, occasional proliferative lesions and inflammatory cells in the prostate during senescence, which were interrupted and/or blocked by treatment with antiangiogenic drugs and finasteride. Decreased AR and Endostatin reactivities, and an increase for ER-α, ER-β and VEGF were seen in the senile group. Decreased VEGF and ER-α reactivities and increased ER-β reactivity were verified in the finasteride, SU5416 groups and especially in SU5416+TNP-470 group. The TNP-470 group showed reduced AR and ER-β protein levels.
The senescence favored the occurrence of structural and/or molecular alterations suggesting the onset of malignant lesions, due to the imbalance in the signaling between the epithelium and stroma. The SU5416+TNP-470 treatment was more effective in maintaining the structural, hormonal and angiogenic factor balance in the prostate during senescence, highlighting the signaling of antiproliferation via ER-β.
Life sciences 05/2014; 106(1). DOI:10.1016/j.lfs.2014.04.027 · 2.70 Impact Factor
"We know ADCR is not unique to the B16 melanoma line as other lines have been reported to grow more slowly in old mice (5–7) and our lab has unpublished data showing that the 4T1 mouse breast cancer cell line and PyMT breast cancer primary cells do not grow as well in old syngeneic mice as in young syngeneic mice (manuscripts in preparation). There are several recent reports of cell lines that have been described to proliferate equally well in young and old syngeneic recipient mice (8,9). This could very well be dependent on the type of mutations in the tumor cells that affect cytokine signaling and cellular cross talk that might attenuate ADCR. "
[Show abstract][Hide abstract] ABSTRACT: A major risk factor for cancer is increasing age, which suggests that syngeneic tumor implants in old mice would grow more rapidly. However, various reports have suggested that old mice are not as permissive to implanted tumor cells as young mice. In order to determine and characterize the age-related response to B16 melanoma, we implanted 5×10(5) tumor cells into 8, 16, 24, and 32-month-old male C57BL/6 (B6) and C57BL/6×BALB/c F1 (CB6 F1) mice subcutaneously in the inguinal and axillary spaces, or intradermally in the lateral flank. Results showed decreased tumor volume with increasing age, which varied according to mouse genetic background and the implanted site. The B6 strain showed robust tumor growth at 8 months of age at the inguinal implantation site, with an average tumor volume of 1341.25 mm(3). The 16, 24, and 32-month age groups showed a decrease in tumor growth with tumor volumes of 563.69, 481.02, and 264.55 mm(3), respectively (p≤0.001). The axillary implantation site was less permissive in 8-month-old B6 mice with an average tumor volume of 761.52 mm(3). The 24- and 32-month age groups showed a similar decrease in tumor growth with tumor volumes of 440 and 178.19 mm(3), respectively (p≤0.01). The CB6F1 strain was not as tumor permissive at 8 months of age as B6 mice with average tumor volumes of 446.96 and 426.91 mm(3) for the inguinal and axillary sites, respectively. There was a decrease in tumor growth at 24 months of age at both inguinal and axillary sites with an average tumor volume of 271.02 and 249.12 mm(3), respectively (p≤0.05). The strain dependence was not apparent in 8-month-old mice injected intradermally with B16 melanoma cells, with average tumor volumes of 736.82 and 842.85 mm(3) for B6 and CB6 F1, respectively. However, a strain difference was seen in 32-month-old B6 mice with an average decrease in tumor volume of 250.83 mm(3) (p≤0.01). In contrast, tumor growth significantly decreased earlier in CB6 F1 mice with average tumor volumes of 417.62 and 216.34 mm(3) in the 16- and 24-month age groups, respectively (p≤0.005). Histologically, implanted tumors in young mice exhibited characteristics of aggressive, rapidly growing tumor cells including high vascularity, mitosis, and invasiveness compared to tumors in old mice. We contend that the decrease in B16 melanoma tumor growth seen with increasing age in B6 and CB6 F1 mice represents a biological process, which we are calling age-dependent cancer resistance (ADCR). Our data provide a detailed description of conditions necessary to use the model to investigate the mechanisms of ADCR and determine its biological and clinical relevance.
"We have shown in aged animals that angiogenesis and tumour growth are inhibited in some solid tumours, such as melanomas, but in prostate cancer equivalent angiogenesis and tumour growth occurred in both young and old animals. Moreover, the prostate tumours had high levels of gelatinase (MMP2 and MMP9) expression and activity (Reed et al, 2007). The relationship between a well-formed matrix and MMP expression is expected as extracellular matrix proteins regulate, in part, the production of the enzymes responsible for their turnover and degradation (Phillips and Bonassar, 2005). "
[Show abstract][Hide abstract] ABSTRACT: Whether tumours are epithelial or non-epithelial in origin, it is generally accepted that once they reach a certain size all solid tumours are dependent upon a vascular supply to provide nutrients. Accordingly, there is great interest in how the extracellular environment enhances or inhibits vascular growth. In this minireview, we will examine key extracellular components, their changes with ageing, and discuss how these alterations may influence the subsequent development of tumour vasculature in the aged host. Because of the tight correlation between advanced age and development of prostate cancer, we will use prostate cancer as the model throughout this review.
British Journal of Cancer 02/2008; 98(2):250-5. DOI:10.1038/sj.bjc.6604144 · 4.84 Impact Factor
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