Notch signaling pathway

The Notch pathway powerfully influences stem cell maintenance, development and cell fate and is appears to play a key roles in cancer. The Notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms. Mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transmembrane receptor protein. It is a hetero-oligomer composed of a large extracellular portion, which associates in a calcium-dependent, non-covalent interaction with a smaller piece of the notch protein composed of a short extracellular region, a single transmembrane-pass, and a small intracellular region.

Notch signaling promotes proliferative signaling during neurogenesis, and its activity is inhibited by Numb to promote neural differentiation. It plays a major role in the regulation of embryonic development. The involvement of Notch signalling in many cancers has led to investigation of notch inhibitors (especially gamma-secretase inhibitors) as cancer treatments.

As of 2013 at least 7 notch inhibitors were in clinical trials. MK-0752 has given promising results in an early clinical trial for breast cancer.

Cancer stem cells (CSC) or “tumor-initiating cells” have been identified in various cancers including breast, colon, hematopoietic, and brain cancer. The CSC population is not only important for tumor initiation, but it is also linked to metastasis, therapy resistance, and recurrence.6 Approaches to target the CSC population can enhance the success of conventional therapies and change the outcomes of treatments. Detailed understanding of the biology of cancer stem cell survival and resistance, and the discovery of specific characteristics of CSCs will open up new possibilities for therapeutic intervention.

Signaling pathways that are critical for stem cell function during development, such as the Wnt, Hedgehog, and Notch pathways are often deregulated in cancers, and promote survival and self-renewal of CSCs. Of these pathways, oncogenic Notch mutations occur in lymphoblastic leukemias, as well as in a variety of solid tumors including breast and non-small-cell lung cancer, colon, and prostate. In breast cancer cells, Notch is linked to aggressive metastatic growth and therapy resistance. Notch signaling has been implicated to regulate the CSC population in several forms of cancer, where it has been shown to be critical for maintenance and self-renewal of CSCs. Notch-targeted therapy is thus an interesting treatment option and several clinical trials have been launched to test efficacy and safety of Notch inhibitors in cancer. Despite the availability of efficient Notch inhibitors such as γ-secretase inhibitors (GSIs), peptides, antibodies or probodies, Notch-related treatments are currently prevented by side effects, due to the requirement for Notch signaling in most tissues. GSI treatment induces diarrhea and suppression of lymphopoiesis. Antibody-based targeting of Notch ligands is associated with induction of vascular tumors in mice27 and a variety of side effects including headache, hypertension, fatigue, right, and left ventricular dysfunction in patients in clinical trials.28 Therefore, clinically efficient suppression of Notch activity requires more targeted delivery strategies, and efficient delivery to CSCs to target Notch signaling in this population.

Nanomaterials for targeted drug delivery to cancer stem cells

Recent developments in cancer biology have identified the existence of a sub-poplulation of cells – cancer stem cells (CSC) that are resistant to most traditional therapies (e.g. chemotherapy and radiotherapy) and have the ability to repair their damaged DNA. These findings have necessitated a break with traditional oncology management and encouraged new perspectives concerning cancer treatment. Understanding the functional biology of CSCs – especially the signaling pathways that are involved in their self-renewal mechanisms – is crucial for discovering new forms of treatment. In this review, we highlight current and future prospects for potential cancer therapies based on the use of nano-sized materials. Nanomaterials could revolutionize cancer management because of their distinctive features – unique surface chemistry, strong electronic, optic, and magnetic properties – that are found neither in bulk materials nor in single molecules. Based on these distinct properties, we believe that nanomaterials could be excellent candidates for use in CSC research in order to optimize cancer therapeutics. Moreover, we propose these nanomaterials for the inhibition of the self-renewal pathways of CSCs by focusing on the Hedgehog, Notch, and Wnt/β-catenin self-renewal mechanisms. By introducing these methods for the detection, targeting, and destruction of CSCs, an efficient alternative treatment for the incurable disease of cancer could be provided.

Nanoparticles target and kill cancer stem cells that drive tumor growth

Many cancer patients survive treatment only to have a recurrence within a few years. Recurrences and tumor spreading are likely due to cancer stem cells that can be tough to kill with conventional cancer drugs. But now researchers have designed nanoparticles that specifically target these hardy cells to deliver a drug. The nanoparticle treatment worked far better than the drug alone in mice.

Dozens of nanomedicines are in clinical trials right now, according to Tsourkas, and a few have been approved by the FDA. One of these is the medicine Doxil, which contains hollow nanoparticles with the cancer drug doxorubicin inside. It’s primarily used to treat ovarian cancer and multiple myeloma, and it was one of the first nanoparticle-based cancer drugs to be approved by the FDA.

Readings and References

Inhibiting Notch Activity in Breast Cancer Stem Cells by Glucose Functionalized Nanoparticles Carrying γ-secretase Inhibitors


N-acetylcysteine negatively regulates Notch3 and its malignant signaling.