CSCs and the Hedgehog pathway

To this day, scientists are still scratching their heads when questioned about the true science behind cancer and it’s causes. A proposed theory, known as “The Stem Cell Theory of Cancer” claims to shed some light behind this mysterious, yet extremely deadly killer, providing an exciting future for scientists working on a cure for cancer.

CSCs, or cancer stem cells, are a type of stem cell that is responsible for the constant regeneration of cancer cells. Essentially, cancer stem cells are theorized to constantly regenerate cancer cells, which in turn attack our bodies over a long period, causing damage. CSCs are developed from regular stem cells, such as stem cells found in our bone marrows. Genetic mutations could possibly cause mutations in the stem cell, which then form a CSC. Similarly, progenitor cells could experience genetic mutations which would give rise to mutated progenitor cells, thus forming a cancer stem cell. Genetic mutations could also cause a fully differentiated cell to de-differentiate and form cancer stem cells.

Like regular stem cells, such as iPSC, cancer stem cells are unspecialized and are able to divide and differentiate to give rise to specialized cancer cells. CSCs can recapitulate tumor heterogeneity since they are found in tumors. CSCs are also able to cause metastases (spread of cancer cells to new areas of the body through bloodstream). Since CSCs are resilient to ionizing radiation, which is widely used in radiotherapy and chemotherapy, CSCs act like a sink for cancer cells, allowing new cancer cells to develop and cause cancer relapse despite treatment.

According to the Stem Cell Theory of Cancer, an original tumor, containing CSCs exposed to conventional cancer treatment will result in the cancer cells dying off, leaving the CSCs behind. Over time, the CSCs aid the growing of new cancer cells, causing tumor relapse. Scientists are currently working on the development of CSC specific cancer therapy, which targets CSCs. With the CSCs killed off in the tumor, the surrounding cancer cells will be permanently eradicated due to loss of viability source.

It is therefore, clear, that specifically targeting CSCs in treatments would yield the most effective results, preventing metastasis and relapse of cancer. Certain pathways have been identified to aid the proliferation and differentiation of CSCs, namely the Hedgehog pathway (Hh).

To understand how the Hh pathway can be targeted to prevent CSCs from developing, one must have a brief understanding of what the Hh pathway really is. The Hh pathway (Hedgehog signaling pathway) is a signaling pathway that controls information transmitted to embryos for proper cell differentiation. Hh pathway activity is much lower in adults compared to embryos and is only active in some sites, such as at the CNS. In a nutshell, the Hh pathway regulates tissue homeostasis, renews and repairs tissues, maintains stem cells in adults. In contrast in embryos, the role of the Hh pathway is significantly different, where the pathway controls cell fate, proliferation, and cell differentiation to ensure formation of a healthy embryo. Mammalian Hh pathways are regulated by 3 Hh homologues: Sonic Hedgehog (Shh), Indian Hedgehog (Ihh) and Desert Hedgehog (Dhh).

Why is the Hh pathway significant? Scientists have recently discovered that the Hh pathway is responsible for tumorigenesis (formation of tumors) through signaling from the tumor to CSCs. Evidence suggests that many tumors and cancers form due to an anomaly in the pathways involved in stem cells, such as the Hh pathway. More recently, the Hh pathway has been found to be responsible for regulating renewal of CSCs of Chronic Myelogenous Leukemia. With this much evidence, scientists have dug deep into finding ways of inhibiting the action of the Hh pathway to prevent such cancers from forming – by using teratogens. The smoothened protein, encoded by SMO gene, is a component of the Hh pathway. For the pathway to work properly, Shh binds to the Patched 1 protein, inhibiting Patched 1 protein’s activity. This activates SMO, which transduces the Hh signal to the cytoplasm.

Teratogens are substances which case abnormalities and malformations in embryos. Specific teratogens exist, such as Cyclopamine, which inhibits the activity of the Hh pathway by binding to the SMO transmembrane receptor protein, preventing Hh signals from being transmitted, thus preventing the formation of cancer stem cells - which would be a massive scientific breakthrough.

As the Hh pathway is still an extremely new discovery in the world of biology, our understanding of how it can be manipulated to treat cancers is still considerably limited. Despite this, progress over the recent years has been rapid and extremely promising. It really is a matter of time before drugs containing Hh inhibitors are prescribed daily to cancer sufferers around the world.

https://med.stanford.edu/ludwigcenter/overview/theory.html

http://www.cardiff.ac.uk/cancer-stem-cell/research/about-cancer-stem-cells

Gupta. S, Takebe. N, LoRusso. P Therapeutic Advances in Medical Oncology

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