[엠디저널] In reality, cancer is not uniform and is composed of different cells, of which only cancer stem cells have the ability to form cancer. Therefore, new cancer treatment strategies are needed.
Anti-cancer drugs have side effects and resistance. Anti-cancer drugs are drugs that inhibit the proliferation and growth of tumor cells by acting on dividing and proliferating cells. Since cancer cells arise from normal cells, their structure, division and cell proliferation are the same as normal cells. For this reason, anticancer drugs have the problem of not being able to distinguish between tumor cells and normal cells and of showing toxicity towards both. As a result, cancer patients undergoing chemotherapy have no choice but to suffer from various side effects, and in many cases, they spend more time treating those side effects or are unable to continue treatment due to the side effects .
During cancer treatment, resistance to cancer drugs develops, which limits the effectiveness of the treatment. Even targeted cancer drugs, known to act only on tumor cells, have side effects and resistance. Cancer is very different from patient to patient, and even an individual patient’s cancer is composed of a heterogeneous group of tumor cells. Therefore, although targeted treatment must be targeted according to the characteristics of the tumor cells, only treatments that kill all tumor cells have been used. If a specific treatment targeting cancer stem cells is developed, the chances of curing cancer patients will greatly increase.
NF-kB is a transcription factor that appears in activated T lymphocytes and in the human body, NF-kB is a key transcription factor of the inflammatory response.
Transcription is the process of converting information in DNA into RNA. DNA, a gene in the nucleus, creates RNA to make proteins. In other words, it enters the nucleus and activates specific genetic regions to produce the necessary proteins. The genome containing the genes is so important that it is well protected inside the nucleus within the cell membrane. When transcription occurs, RNA with a structure complementary to DNA is created and leaves the nucleus to synthesize proteins that perform specific functions.
NF-kB usually exists in the cytoplasm and is attached to IkB, so its activity is suppressed. However, when receiving external stimulation such as tumor necrosis factor (TNF-α) or reactive oxygen species (ROS), NF-κB is activated by separating from the inhibitory protein IκB. The activated NF-κB moves into the nucleus and binds to specific DNA, thus expressing pro-inflammatory genes.
These proinflammatory genes include inflammatory cytokines such as interleukin-1 (IL-1), IL-2, IL-6, IL-8, TNF-α, cyclooxygenase-2 (COX-2), etc. Mesenchymal stem cells (MSCs) secrete inflammatory cytokines IL-1, IL-2, IL-6, and IL-8, causing persistent inflammation. Continued inflammation can cause mesenchymal stem cells to deform, causing them to transform into cancer cells.
NF-κB, a transcription factor that causes inflammation, can transform normal cells into malignant tumor cells by causing continuous inflammation, promotes the creation of cancer stem cells, and creates a favorable environment for tumor cell survival. NF-κB promotes anaerobic glycolysis, a metabolic pattern typical of tumor cells, and plays a role in supporting tumor cell growth and proliferation. NF-κB works by suppressing cancer suppressor genes such as p53 while activating oncogenes such as ras and myc.
NF-κB prevents cells from dying by activating genes that suppress apoptosis. Consequently, NF-κB acts as a master switch in two areas: inflammatory expression and cancer stem cell gene expression. Furthermore, NF-κB participates in tumor promotion between various cancer-causing stages by expressing proinflammatory genes and producing various inflammatory mediators.
Therefore, it can be thought that inhibition of NF-κB, a transcription factor that causes inflammation, could prevent the cancerization process or significantly prevent cancer recurrence and metastasis. NF-κB is attached to IκB in the cytoplasm and its activity is suppressed. When IκB is phosphorylated and removed, NF-κB is separated from IκB and moves into the nucleus. Additionally, curcumin, a component of turmeric, prevents NF-κB from moving into the nucleus by inhibiting IκB kinase, an enzyme that phosphorylates IκB. Curcumin is the main ingredient in curry, as we commonly know it.
The process by which epithelial cells undergo morphological transformation into tumor cells is called epithelial-mesenchymal transition (EMT). When epithelial-mesenchymal transition is promoted, fixed cells separate and become capable of movement. When epithelial-mesenchymal transition occurs, the cell shape becomes fluid and does not adhere well to other places, and cancer metastasis begins. The cancer suppressor gene p53 activates micro RNA that restores epithelial-mesenchymal transition to epithelial cells.
Resveratrol, an antioxidant from grape skin, catechin from green tea extract (epigallocatechin gallate, EGCG), diallyl sulfide from garlic, and sulforaphane from broccoli, all readily available around us, help activate p53 .
In particular, sulfur substances contained in garlic and broccoli have the effect of detoxifying carcinogens by activating detoxifying enzymes that remove carcinogens, thus producing an anti-tumor effect. It works by preventing the onset of cancer early.
The area where tumor cells initially form, 150 to 200 μm from the blood vessel, becomes a hypoxic area, and when hypoxia occurs, tumor cells transform into tumor stem cells.
How can cancer cells in a hypoxic area transform into cancer stem cells?
In environments where oxygen is scarce and difficult to survive, cancer cells transform into cancer stem cells to survive. Changes in the surrounding microenvironment are strongly involved in the formation of cancer stem cells, which are the source of many tumors. This is caused by abnormally activated embryonic stem cell genes (Oct-4, Wnt, Hedgehog, Notch, etc.).
In the early stages of fetal development, a fertilized egg that combines a sperm and an egg divides and proliferates in an oxygen-free environment. The division and proliferation of an embryo is carried out by Oct-4, Wnt, Hedgehog and Notch obtained through the expression of embryonic stem cell genes.
To preserve life, tumor cells in hypoxic areas also express embryonic stem cell genes such as Oct-4, Wnt, Hedgehog and Notch, which are expressed in embryos and become tumor stem cells. NF-κB plays a role in the creation of cancer stem cells by promoting embryonic stem cell gene expression. On the other hand, sulforaphane from broccoli and curcumin from curry inhibit Wnt activity. These phytochemicals suppress cancer recurrence or metastasis by inhibiting abnormally activated signaling in cancer stem cells.
Recurrence or metastasis is caused by cancer stem cells.
In traditional cancer treatment, all attention has been focused on simply eliminating cancer cells, and cancer stem cells have been relatively neglected as a treatment target. In some tumors, chemotherapy can temporarily kill tumor cells to some extent, but a small number of tumor stem cells do not die despite chemotherapy or radiation treatment, they survive and remain dormant, and then relapse and metastasize to other parts of the body. Even if only one cancer stem cell survives, over time it will completely relapse into a more aggressive malignancy. Therefore, a real cancer treatment should not only aim to kill cancer cells, but also to completely eliminate cancer stem cells before they start to proliferate again into a new form and cause more serious problems. If the cancer stem cells are completely killed, the cancer will be completely eliminated and the patient will recover completely.
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