👤 Melvin Anyasi Ambele

The role of mesenchymal stromal/stem cells (MSCs) in tumour development and progression remains a subject of debate. Previous studies have reported contradictory outcomes, possibly due to variations in experimental design and the use of xenograft models. Xenograft models limit interpretation and translation due to cross-species variability. To address these limitations, we employed an isogenic mouse model of spontaneous breast cancer (BC) to investigate the impact of murine MSCs on BC development and progression. MSCs isolated from FVB/N mouse adipose tissue (mASCs) were administered to female mice with palpable mammary tumours. Tumour volume and mass were assessed, and analysis of histopathological necrosis and gene expression was conducted on mammary (MT) and lung metastatic tumours (LT). No change in MT mass and volume was observed between mASC-treated and control mice. However, mASC treatment led to increased necrosis in LT but not in MT. Immunohistochemistry revealed that mASC-treated mice had fewer CD163+ anti-inflammatory macrophages in the LT but not in the MT. Tgf-β3, vegfr1, and cd105 were observed and downregulated in both MT and LT in mASC-treated mice. The downregulation of cd36 and tgf-β3 contributes to pro-tumourigenic activities, whereas the downregulation of vegfr1 and cd105 is associated with an anti-tumour effect. In the mASC treatment group, all cytokines tested for, except IL-27, were elevated. This study suggests that mASCs are anti-tumourigenic in pulmonary metastatic BC. Our findings emphasize the importance of considering the tumour microenvironment and employing relevant animal models when investigating the impact of MSCs on tumour progression. Show less

The anti-cancer agent 2-methoxyestradiol (2-ME) has been shown to have anti-proliferative and anti-angiogenic properties. Previously, the effect of 2-ME on early- and late-stage breast cancer (BC) was investigated in vivo using a transgenic mouse model (FVB/N-Tg(MMTV-PyVT)) of spontaneous mammary carcinoma. Anti-tumor effects were observed in late-stage BC with no effect on early-stage BC. Given the contrasting results obtained from the different BC stages, we have now investigated the effect of 2-ME when administered before the appearance of palpable tumors. Each mouse received 100 mg/kg 2-ME on day 30 after birth, twice per week for 28 days, while control mice received vehicle only. Animals were terminated on day 59. Lung and mammary tissue were obtained for immunohistochemical analysis of CD163 and CD3 expression, and histological examination was performed to analyze tumor necrosis. Additionally, blood samples were collected to measure plasma cytokine levels. 2-ME increased tumor mass when compared to the untreated animals (p = .0139). The pro-tumorigenic activity of 2-ME was accompanied by lower CD3+ T-cell numbers in the tumor microenvironment (TME) and high levels of the pro-inflammatory cytokine interleukin (IL)-1β. Conversely, 2-ME-treatment resulted in fewer CD163+ cells detectable in the TME, increased levels of tumor necrosis, increased IL-10 plasma levels, and low IL-6 and IL-27 plasma levels. Taken together, these findings suggest that 2-ME promotes early-stage BC development. Show less

We have undertaken an in-depth transcriptome analysis of adipogenesis in human adipose-derived stromal cells (ASCs) induced to differentiate into adipocytes in vitro. Gene expression was assessed on days 1, 7, 14 and 21 post-induction and genes differentially expressed numbered 128, 218, 253 and 240 respectively. Up-regulated genes were associated with blood vessel development, leukocyte migration, as well as tumor growth, invasion and metastasis. They also shared common pathways with certain obesity-related pathophysiological conditions. Down-regulated genes were enriched for immune response processes. KLF15, LMO3, FOXO1 and ZBTB16 transcription factors were up-regulated throughout the differentiation process. CEBPA, PPARG, ZNF117, MLXIPL, MMP3 and RORB were up-regulated only on days 14 and 21, which coincide with the maturation of adipocytes and could possibly serve as candidates for controlling fat accumulation and the size of mature adipocytes. In summary, we have identified genes that were up-regulated only on days 1 and 7 or days 14 and 21 that could serve as potential early and late-stage differentiation markers. Show less