Tumor Microenvironment Uses a Reversible Reprogramming of Mesenchymal Stromal Cells to Mediate Pro-tumorigenic Effects

The role of mesenchymal stromal cells (MSCs) in the tumor microenvironment is well described. Available data support that MSCs display anticancer activities, and that their reprogramming by cancer cells in the tumor microenvironment induces their switch toward pro-tumorigenic activities. Here we discuss the recent evidence of pro-tumorigenic effects of stromal cells, in particular (i) MSC support to cancer cells through the metabolic reprogramming necessary to maintain their malignant behavior and stemness, and (ii) MSC role in cancer cell immunosenescence and in the establishment and maintenance of immunosuppression in the tumor microenvironment. We also discuss the mechanisms of tumor microenvironment mediated reprogramming of MSCs, including the effects of hypoxia, tumor stiffness, cancer-promoting cells, and tumor extracellular matrix. Finally, we summarize the emerging strategies for reprogramming tumor MSCs to reactivate anticancer functions of these stromal cells

Emerging data supporting stromal cell therapeutic potential in cancer: reprogramming stromal cells of the tumor microenvironment for anti-cancer effects

After more than a decade of controversy on the role of stromal cells in the tumor microenvironment, the emerging data shed light on pro-tumorigenic and potential anti-cancer factors, as well as on the roots of the discrepancies. We discuss the pro-tumorigenic effects of stromal cells, considering the effects of tumor drivers like hypoxia and tumor stiffness on these cells, as well as stromal cell-mediated adiposity and immunosuppression in the tumor microenvironment, and cancer initiating cells' cellular senescence and adaptive metabolism. We summarize the emerging data supporting stromal cell therapeutic potential in cancer, discuss the possibility to reprogram stromal cells of the tumor microenvironment for anti-cancer effects, and explore some causes of discrepancies on the roles of stromal cells in cancer in the available literature

Developmental pathways associated with cancer metastasis: Notch, Wnt, and Hedgehog

Master developmental pathways, such as Notch, Wnt, and Hedgehog, are signaling systems that control proliferation, cell death, motility, migration, and stemness. These systems are not only commonly activated in many solid tumors, where they drive or contribute to cancer initiation, but also in primary and metastatic tumor development. The reactivation of developmental pathways in cancer stroma favors the development of cancer stem cells and allows their maintenance, indicating these signaling pathways as particularly attractive targets for efficient anticancer therapies, especially in advanced primary tumors and metastatic cancers. Metastasis is the worst feature of cancer development. This feature results from a cascade of events emerging from the hijacking of epithelial-mesenchymal transition, angiogenesis, migration, and invasion by transforming cells and is associated with poor survival, drug resistance, and tumor relapse. In the present review, we summarize and discuss experimental data suggesting pivotal roles for developmental pathways in cancer development and metastasis, considering the therapeutic potential. Emerging targeted antimetastatic therapies based on Notch, Wnt, and Hedgehog pathways are also discussed

Anti-androgenic, anti-oestrogenic and antioxidant activities of aqueous extract of Laportea ovalifolia on adults rats.

Cancer is one of the most life-threatening diseases in which deregulating proliferation of abnormal cells invades and disrupts surrounding tissues. It constitutes seriouspublic health problems in both developed and developing countries.To evaluate the anti-androgenic, anti-estrogenic and antioxidant activities of Laportea ovalifolia (L. ovalifolia) in order to contribute to the search and the valorization of medicinal plants which could reduce mortality related to prostate cancer.The evaluation of the anti-androgenic activity were carried out on castrated male rats receiving simultaneous daily administration of testosterone and different doses of aqueous extract of L. Ovalifolia during a period of 10 days. That of the anti-estrogenic activity was carried out on mature ovariectomized female rats receiving for a week simultaneous daily administration of estradiol and different doses of plant extract. The evaluation of the in vivo antioxidant activity of L. Ovalifolia aqueous extract was carried on adult male rats receiving simultaneous daily administration of naphthalene and different doses of extract, for 15 days. For its in vitro antioxidant activity, the amounts of phenolic compounds in plant extracts were determined as well as the total flavonoid contents of the crude extracts. Also, the DPPH scavenging activity of the plant extract was determined as well as its reducing power.As compare to the 0 mg/kg testosterone primed castrated rat, those treated with the various dose of the plant extract presented either a significant decrease in weights of all their reproductive tissues (P˂0.01 - P˂0.001) or a significant increase (P˂0.001) in their serum level of testosterone. For all the plant extract treated ovariectomized rats, similar trends were observed for the relative uteri weight (P˂0.01) and that of the serum level of estradiol (P˂0.001). Plant extract contains 13.33±0.1 mg GAE/g and 05.27±0.17 mg CATE/g of phenolic and flavonoids compounds respectively and exhibits DPPH radical scavenging ability as well as ferric-reducing antioxidant power. Relatively to animals treated at 0 mg/kg, the various doses of the plant extract significantly increased (P˂0.05 - P˂0.001) the activity of catalase (in liver, lungs and the serum), SOD (in liver and heart) and peroxidase (in liver, heart, serum and lungs). It also significantly reduces (P˂0.001) the level of nitric oxide in the liver, heart, lungs, kidneys and serum.Globally, these results denote the anti-androgenic, anti-estrogenic and antioxidant potential of L. ovalifolia. 

Anti-androgenic, anti-oestrogenic and antioxidant activities of aqueous extract of Laportea ovalifolia on adults rats.

Cancer is one of the most life-threatening diseases in which deregulating proliferation of abnormal cells invades and disrupts surrounding tissues. It constitutes seriouspublic health problems in both developed and developing countries.To evaluate the anti-androgenic, anti-estrogenic and antioxidant activities of Laportea ovalifolia (L. ovalifolia) in order to contribute to the search and the valorization of medicinal plants which could reduce mortality related to prostate cancer.The evaluation of the anti-androgenic activity were carried out on castrated male rats receiving simultaneous daily administration of testosterone and different doses of aqueous extract of L. Ovalifolia during a period of 10 days. That of the anti-estrogenic activity was carried out on mature ovariectomized female rats receiving for a week simultaneous daily administration of estradiol and different doses of plant extract. The evaluation of the in vivo antioxidant activity of L. Ovalifolia aqueous extract was carried on adult male rats receiving simultaneous daily administration of naphthalene and different doses of extract, for 15 days. For its in vitro antioxidant activity, the amounts of phenolic compounds in plant extracts were determined as well as the total flavonoid contents of the crude extracts. Also, the DPPH scavenging activity of the plant extract was determined as well as its reducing power.As compare to the 0 mg/kg testosterone primed castrated rat, those treated with the various dose of the plant extract presented either a significant decrease in weights of all their reproductive tissues (P˂0.01 - P˂0.001) or a significant increase (P˂0.001) in their serum level of testosterone. For all the plant extract treated ovariectomized rats, similar trends were observed for the relative uteri weight (P˂0.01) and that of the serum level of estradiol (P˂0.001). Plant extract contains 13.33±0.1 mg GAE/g and 05.27±0.17 mg CATE/g of phenolic and flavonoids compounds respectively and exhibits DPPH radical scavenging ability as well as ferric-reducing antioxidant power. Relatively to animals treated at 0 mg/kg, the various doses of the plant extract significantly increased (P˂0.05 - P˂0.001) the activity of catalase (in liver, lungs and the serum), SOD (in liver and heart) and peroxidase (in liver, heart, serum and lungs). It also significantly reduces (P˂0.001) the level of nitric oxide in the liver, heart, lungs, kidneys and serum.Globally, these results denote the anti-androgenic, anti-estrogenic and antioxidant potential of L. ovalifolia. 

In vitro cytotoxicity studies of sixteen plants used for pregnant women’s health conditions in Menoua Division-West Cameroon

In Cameroon, many plants are used in traditional medicine for the treatment of pregnancy and childbirth complaints. However, toxicological potential of most of these plants have not been investigated. In order to evaluate the degree of safety of their users, in vitro cytotoxic potentials of sixteen of these medicinal plants were subjected to the assay using the brine shrimp lethality assay. From this study, the aqueous extract of plant Rauvolfia vomitoria bark was found to be cytotoxic and that of Ageratum conyzoides stem and leaves slightly cytotoxic, with LC50 values of 17.62 and 99.17µg/ml, respectively. The least toxic plant extracts were Aloe buttneri, Commelina benghalensis, Ipomoea tenuirostrisandNelsonia canescens, (LC50 value > 105 µg/ml). Overall fourteen extracts were found to be non-toxic. Most herbal remedies were non cytotoxic but it would be necessary to complete these cyto-toxicological information by mutagenicity, teratogenicity tests as welle as in vivo toxicological tests on animals

In vitro cytotoxicity studies of sixteen plants used for pregnant women’s health conditions in Menoua Division-West Cameroon

In Cameroon, many plants are used in traditional medicine for the treatment of pregnancy and childbirth complaints. However, toxicological potential of most of these plants have not been investigated. In order to evaluate the degree of safety of their users, in vitro cytotoxic potentials of sixteen of these medicinal plants were subjected to the assay using the brine shrimp lethality assay. From this study, the aqueous extract of plant Rauvolfia vomitoria bark was found to be cytotoxic and that of Ageratum conyzoides stem and leaves slightly cytotoxic, with LC50 values of 17.62 and 99.17µg/ml, respectively. The least toxic plant extracts were Aloe buttneri, Commelina benghalensis, Ipomoea tenuirostrisandNelsonia canescens, (LC50 value > 105 µg/ml). Overall fourteen extracts were found to be non-toxic. Most herbal remedies were non cytotoxic but it would be necessary to complete these cyto-toxicological information by mutagenicity, teratogenicity tests as welle as in vivo toxicological tests on animals

A new phenyl alkyl ester and a new combretin triterpene derivative from Combretum fragrans F. Hoffm (Combretaceae) and antiproliferative activity

This work concerns the isolation and structure elucidation of compounds obtained from the extract of leaves and stem bark of Combretum fragrans F. Hoffm. Both extracts and some isolated compounds were tested for antiproliferative activity on glioblastoma (U87MG and C6 cells) and prostate (PC-3 cells) cancer cell lines using XTT (2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxyanilide inner salt) assay. The dichloromethane/methanol (1:1) extract of the leaves led to the isolation of two new compounds such as fragransinate (1) and combretin C (2), alongside five known compounds such as combretin A (3), belamcanidin (4), cirsilineol (5), velutin (6), and a mixture of β-sitosterol-3-O-β-d-glucopyranoside (10a) and stigmasterol-3-O-β-d-glucopyranoside (10b), whereas the methanol extract of the stem bark led to the isolation of three known compounds betulinic acid (7), bellericagenin B (8), and a mixture of β-sitosterol (9a) and stigmasterol (9b). The structure of compounds was elucidated by nuclear magnetic resonance and mass spectrometry data. The methanol extract of the stem bark showed a powerful antiproliferative activity on all tested cells, as well as the extract of leaves which also showed important cytotoxicity effect. Compound (3) showed good antiproliferative activity particularly on U87MG and PC-3 cells, whereas compound (5) exhibits moderated activity. Compounds (2) and (8) were not active on all tested cells

Euphol from Tapinanthus sp. Induces Apoptosis and Affects Signaling Proteins in Glioblastoma and Prostate Cancer Cells

International audienceBackground: Plants play an important role in cancer therapy. They are source of natural molecules which can induce apoptosis in cancer cells by affecting molecular mechanisms implicated in cancer progression. The MAP Kinase/ERK1/2 and PI3K/AKT signaling pathways are two classical signaling pathways implicated in cancer progression and constitute therapeutic targets against cancer. This study aimed to evaluate the effect of euphol on MAP Kinase/ERK1/2 and PI3K/AKT signaling pathways in glioblastoma and prostate cancer cells. Euphol is a tetracyclique triterpene alcohol isolated from Tapinanthus sp. which is a hemi parasitic plant belonging to Loranthaceae family. Methods: Plant powder was extracted by maceration and euphol was isolated and described using respectively column chromatography separation on silica gel and spectroscopic data. Cytotoxic effect of euphol was evaluated using XTT assay and its effect on MAP Kinase/ERK1/2 and PI3K/AKT protein expression was investigated by Western immunoblot analysis. Apotosis was analyzed by evaluating caspase-3/7 activity. Results: Our investigations demonstrated that this compound has an important cytotoxic effect on C6 and U87 MG glioblastoma (GBM) cells and PC-3 prostate cancer cells. Furthermore, euphol-induced apoptosis revealed by elevated caspase 3/7 activity, was correlated with a significant inhibition of MAP kinase/Erk 1/2 and PI3K/Akt signaling pathway in glioblastoma U87 MG cells. The reverse effect was observed in C6 glioblastoma cells, where apoptosis was correlated with a long-lasting activation of Erk 1/2. In PC-3 cells, euphol had no or limited effect on Erk 1/2 and Akt activity. Conclusion: These results indicate that euphol induces cell death in glioblastoma and prostate cancer cells and regulates significantly Erk1/2 and Akt activity in glioblastoma cells