Prostate cancer cell proliferation and angiogenesis in different obese mice models

Abstract

Obesity has been associated with increased incidence and aggressiveness of prostate cancer. Although controversial, several studies suggest that leptin could influence tumour cell growth and proliferation. The main goal of this study was to assess cellular growth of prostate adenocarcinoma cells in obese mice with different endogenous hormonal environments in what relates to leptin circulating levels and sensitivity. Four groups of mice (n = 6/group) were used, namely obese mice with congenital non-functioning leptin receptor OBR (db/db), obese mice with congenital leptin deficiency (ob/ob), mice with diet induced obesity (DIO) and normal weight C57BL/6J mice (control). All groups of mice were injected subcutaneously with 3.0 x 10(5) RM1 cells/500 microl PBS (murine prostate carcinoma androgen insensitive cells) and tumour growth and angiogenesis were evaluated 14 days after inoculation. The tumours induced in ob/ob and DIO mice were significantly larger (P < 0.001) while those induced in db/db mice were significantly smaller (P = 0.047), when compared with controls. Morphometric analysis revealed that mitotic index and Ki-67 positive nuclear density, both cell proliferation markers, were also significantly lower in the tumours of db/db mice (P < 0.001) when compared to controls. An inverse correlation was observed between leptin plasma levels and tumour weight (r = -0.642, P < 0.001), mitotic index (r = -0.646, P < 0.01) and Ki-67 positive nuclear density (r = -0.795, P < 0.001). These results suggest that high leptin concentrations are not favourable to RM1 cell growth and proliferation. On the contrary, high plasma leptin levels were associated with less cellular proliferation and angiogenesis in vivo.

Expression of p27Kip1, a cell cycle repressor protein, is inversely associated with potential carcinogenic risk in the genetic rodent models of obesity and long-lived Ames dwarf mice

“…Our observations were also generally consistent with the results of the studies where RM1 murine prostate cancer cells were injected subcutaneously into the obese ob/ob and db/db mice [8]. Our observations were, however, only partially consistent with the results of the studies where MMTV-Wnt-1 mammary tumors were orthotopically transplanted into the right mammary fat pad of obese ob/ob and db/db mice [9].…”

“…These changes were, however, not entirely consistent with the reported risk of developing cancer in homozygous leptin-deficient obese ob/ob mice [8,9]. On the one hand, our observations were generally consistent with the results of the previously reported study where RM1 murine prostate cancer cells were injected subcutaneously into the obese ob/ob mice [8]. This study found positive associations among obesity, cancer and the serum levels of insulin.…”

“…They were also controversial with homozygous leptin receptor-deficient obese db/db mice. On the one hand, it was reported that negative associations were found between obesity and cancer in the study where RM1 murine prostate cancer cells were injected subcutaneously into the obese db/db mice [8]. This study found that the serum levels of insulin in both obese db/db mice and lean control mice were low and not statistically different from each other [8].…”

“…On the one hand, it was reported that negative associations were found between obesity and cancer in the study where RM1 murine prostate cancer cells were injected subcutaneously into the obese db/db mice [8]. This study found that the serum levels of insulin in both obese db/db mice and lean control mice were low and not statistically different from each other [8]. On the other hand, it was also reported that neither positive nor negative associations were found between obesity and cancer in the study where MMTV-Wnt-1 mammary tumors were orthotopically transplanted into the right mammary fat pad of obese db/db mice, although the serum levels of insulin were significantly higher in obese db/db mice compared with the lean control mice [9].…”

“…On the one hand, it was reported that the RM1 murine prostate cancer cells, injected subcutaneously into the obese ob/ob mice, were significantly larger compared with lean control mice [8]. On the other hand, it was also reported that the growth of the MMTV-Wnt-1 mammary tumors, orthotopically transplanted into the right mammary fat pad of obese ob/ob mice, were suppressed compared with lean control mice [9].…”