Since their description and identification in leukemias and solid tumors, cancer stem cells (CSC) have been the subject of intensive research in translational oncology. Indeed, recent advances have led to the identification of CSC markers, CSC targets, and the preclinical and clinical evaluation of the CSC-eradicating (curative) potential of various drugs. However, although diverse CSC markers and targets have been identified, several questions remain, such as the origin and evolution of CSC, mechanisms underlying resistance of CSC against various targeted drugs, and the biochemical basis and function of stroma cell-CSC interactions in the so-called ‘stem cell niche.’ Additional aspects that have to be taken into account when considering CSC elimination as primary treatment-goal are the genomic plasticity and extensive subclone formation of CSC. Notably, various cell fractions with different combinations of molecular aberrations and varying proliferative potential may display CSC function in a given neoplasm, and the related molecular complexity of the genome in CSC subsets is considered to contribute essentially to disease evolution and acquired drug resistance. In the current article, we discuss new developments in the field of CSC research and whether these new concepts can be exploited in clinical practice in the future.

Breast cancer is one of the most prevalent and devastating malignant diseases in women worldwide. Fortunately, while breast cancer incidence is still increasing, its death rate is declining. This is mainly due to early diagnosis and potent therapies such as blockade of estrogen receptor- or of ErbB2 (HER2-neu) membrane receptorsignaling. In recent years, the PI3K/AKT/mTOR pathway, which transmits signals from the cell membrane into the nucleus and activates multiple oncogenic programs, has been found to play a crucial role in the regulation of breast cancer cell growth. This pathway is densely interconnected with a multitude of other important regulatory systems for glucose-, lipid- and amino acid-metabolism, for energy balance, and for autophagy. It has been found that PI3K/AKT/mTOR signaling modulates estrogen receptor function. Using transverse and feedback regulatory loops the PI3K/AKT/mTOR cascade can communicate with concurrent and with upstream systems. Thus, PI3K/AKT/mTOR is a crucial element within a complicated signaling network. This pathway is hyperactive in more than 70% of breast tumors. Hence, the protein kinases located along this route represent very attractive and promising drug targets for breast cancer therapy. Currently, numerous small molecular drugs that inhibit PI3K, AKT and/or mTOR are being developed in preclinical and clinical models of breast cancer. Some of these compounds are highly selective blocking only one particular kinase complex, whereas others interfere with two (mTORC1+mTORC2) or even three effectors (PI3K+mTORC1+mTORC2) of the pathway. Due to the many interactions with other regulatory systems, silencing of the pathway can cause unexpected results. Therefore, detailed preclinical and clinical evaluation of these compounds as single drugs and in combination is required to achieve optimal results with maximal clinical benefit and acceptable toxicity. Also, reliable biomarkers for the identification of patient subsets that will maximally benefit from PI3K/AKT/mTOR inhibition need to be developed. Thus, selective silencing of PI3K/AKT/mTOR signaling represents a promising approach for breast cancer and might prove useful when combined with other drugs. Here we review the current preclinical and clinical data and compare the potential benefits of multi- versus single-targeting PI3K/AKT/mTOR drugs.

Ovarian cancer (OC) is caused by genetic aberrations in networks that control growth and survival. Importantly, aberrant cancer metabolism interacts with oncogenic signaling providing additional drug targets. Tumors overexpress the lipogenic enzyme fatty acid synthase (FASN) and are inhibited by FASN blockers, whereas normal cells are FASN‐negative and FASN‐inhibitor‐resistant. Here, we demonstrate that this holds true when ovarian/oviductal cells reside in their autochthonous tissues, whereas in culture they express FASN and are FASN‐inhibitor‐sensitive. Upon subculture, nonmalignant cells cease growth, express senescence‐associated β‐galactosidase, lose FASN and become FASN‐inhibitor‐resistant. Immortalized ovarian/oviductal epithelial cell lines—although resisting senescence—reveal distinct growth activities, which correlate with FASN levels and FASN drug sensitivities. Accordingly, ectopic FASN stimulates growth in these cells. Moreover, FASN levels and lipogenic activities affect cellular lipid composition as demonstrated by thin‐layer chromatography. Correlation between proliferation and FASN levels was finally evaluated in cancer cells such as HOC‐7, which contain subclones with variable differentiation/senescence and corresponding FASN expression/FASN drug sensitivity. Interestingly, senescent phenotypes can be induced in parental HOC‐7 by differentiating agents. In OC cells, FASN drugs induce cell cycle blockade in S and/or G2/M and stimulate apoptosis, whereas in normal cells they only cause cell cycle deceleration without apoptosis. Thus, normal cells, although growth‐inhibited, may survive and recover from FASN blockade, whereas malignant cells get extinguished. FASN expression and FASN drug sensitivity are directly linked to cell growth and correlate with transformation/differentiation/senescence only indirectly. FASN is therefore a metabolic marker of cell proliferation rather than a marker of malignancy and is a useful target for future drug development.

Multi-level suppression of receptor-PI3K-mTORC1 by fatty acid synthase inhibitors is crucial for their efficacy against ovarian cancer cells Multi-level suppression of receptor-PI3K-mTORC1 by fatty acid synthase inhibitors is crucial for their efficacy against ovarian cancer cells