The effects of aging on tumor growth and angiogenesis are tumor-cell dependent
ABSTRACT 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.
SourceAvailable from: Larissa Akemi Kido[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; DOI:10.1016/j.lfs.2014.04.027 · 2.30 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Aging is considered one of the main predisposing factors for the development of prostate malignancies. Angiogenesis is fundamental for tumor growth and its inhibition represents a promising therapeutic approach in cancer treatment. Thus, we sought to determine angiogenic responses and the effects of antiangiogenic therapy in the mouse prostate during late life, comparing these findings with the prostatic microenvironment in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model. Male mice (52 week-old FVB) were submitted to treatments with SU5416 (6 mg/kg; i.p.) and/or TNP-470 (15 mg/kg; s.c.). Finasteride was administered (20 mg/kg; s.c.), alone or in association to both inhibitors. The dorsolateral prostate was collected for VEGF, HIF-1α, FGF-2 and endostatin immunohistochemical and Western Blotting analyses and for microvessel density (MVD) count. Senescence led to increased MVD and VEGF, HIF-1α and FGF-2 protein levels in the prostatic microenvironment, similarly to what was observed in TRAMP mice prostate. The angiogenic process was impaired in all the treated groups, demonstrating significantly decreased MVD. Antiangiogenic and/or finasteride treatments resulted in decreased VEGF and HIF-1α levels, especially following TNP-470 administration, either alone or associated to SU5416. The combination of these agents resulted in increased endostatin levels, regardless of the presence of finasteride. Prostatic angiogenesis stimulation during senescence favored the development of neoplastic lesions, considering the pro-angiogenic microenvironment as a common aspect also observed during cancer progression in TRAMP mice. The combined antiangiogenic therapy was more efficient, leading to enhanced imbalance towards angiogenic inhibition in the organ. Finally, finasteride administration might secondarily upregulate the expression of pro-angiogenic factors, pointing to the harmful effects of this therapy. Prostate © 2014 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc.The Prostate 04/2015; 75(5). DOI:10.1002/pros.22934 · 3.57 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Antiangiogenic therapies in cancer exert their effects in the context of age-related comorbidities, which affect the entirety of the vascular system. Among those conditions, the impact of atherosclerosis is especially prevalent, but poorly understood, and not reflected in mouse models routinely used for testing antiangiogenic therapeutics. Our earlier work suggested that these obstacles can be overcome with the use of atherosclerosis-prone ApoE-/- mice harbouring syngeneic transplantable Lewis Lung Carcinoma (LLC). Here we report that, sunitinib, the clinically approved, antiangiogenic inhibitor impedes global tumor growth to a greater extent in aged then in young mice. This activity was coupled with changes in the tumor microenvironment, which in aged mice was characterized by pronounced hypoxia, reduction in microvascular density (MVD) and lower pericyte coverage, relative to young controls. We also detected soluble VEGR2 in plasma of sunitinib treated mice. Interestingly, sunitinib modulated tumor infiltration with bone marrow-derived cells (CD45+), recruitment of M2-like macrophages (CD163+) and activation of inflammatory pathways (phospho-STAT3) in a manner that was age-dependent. We suggest that age and atherosclerosis may alter the effects of sunitinib on the tumor microenvironment, and that these considerations may also apply more broadly to other forms of antiangiogenic treatment in cancer.Mechanisms of Ageing and Development 07/2014; DOI:10.1016/j.mad.2014.07.003 · 3.51 Impact Factor