Cancer stem cell
Why does cancer recur?
Already in 1877, Virchow’s student Cohnheim noticed this cell population and pointed out that it possesses an embryonic character*. Today, those cells are called cancer stem cells (CSCs) or tumor-initiating cells (TICs) and are seen as drivers of tumor establishment and growth, often correlated to aggressive, heterogeneous and therapy-resistant tumors. Upon application of therapeutic regimens such as chemo- or radiotherapy the composition of tumor cell subpopulations changes. At first, tumor cells with a high proliferative capacity are targeted and depleted causing a decrease in tumor size while CSCs survive. Additionally, some tumor cells will become senescent [therapy-induced senescence (TIS)], and subsequently can cause a change in the tumor microenvironment (TME) with tumor promoting effects due to the senescence-associated secretory phenotype (SASP).
It is well-known that CSCs are resistant to treatment and can cause tumor relapses. However, under the therapeutic pressure and changed microenvironment CSCs can be newly generated. In this case, these cells do originate from non-CSCs or from therapy-induced senescent tumor cells. It is therefore of importance to characterize these cells in detail and to understand their origin at the time of tumor initiation and tumor relapse. Cancer stem cells are estimated to account for 0.1-1% of the total number of cancer cells.
Tumor initiation can either be driven by transformed differentiated cells or transformed tissue resident stem cells. The transformation can take place during tissue regeneration and can additionally, be initiated and/or accelerated as a response to infections, toxins, radiation or metabolic influences causing mutations. During the transformation process, oncogenes are overexpressed and tumor suppressors are inactivated promoting uncontrolled growth of the cell. As a consequence, cells de-differentiate and acquire stem cell characteristics. The transformation of tissue resident stem cells or their progeny is believed to presuppose a different set of genomic changes allowing uncontrolled, niche-independent proliferation. As stem cells already possess unlimited growth potential, it is believed that the transformation of stem cells and their progeny requires only few genomic changes
Recurrence of cancer is mostly due to cancer stem cells. Cancer develops when genes in normal cells of the human body are mutated due to environmental causes. Then, in order for cancer to adapt to various environments and grow and differentiate, cancer cells mutate their DNA again and develop into stem cells so that they can divide to suit various environments.
To date, there is no anticancer drug that can completely kill cancer stem cells (adult cells). 1st-generation cytotoxic anti-cancer drugs, 2-generation targeted anti-cancer drugs, 3-generation immuno-anticancer drugs, and ADC (anti body drug conjugates) target anti-cancer drugs upgraded from targeted anti-cancer drugs are not possible.
The reason is that cancer stem cells have to metabolize to do something in response to cancer cells, such as monoclonal antibodies or whatever. During chemotherapy, many other cancer cells can be killed by the anticancer drug, but cancer stem cells are still alive and do not metabolize. These stem cells start metabolism again at any time when the conditions are right several years after chemotherapy, and create different cancer cells from the previous one. This is called cancer recurrence. It means that it has DNA completely different from the DNA of the previous cancer and actively replicates again. So, if it recurs, it is often witnessed around many cases where anticancer drugs do not work well and are struggling.
All cancers have their own stem cells that are characteristic of that cancer.
The use of biomarkers in diagnosis, therapy and prognosis has gained increasing interest over the last decades. In particular, the analysis of biomarkers in cancer patients within the pre- and post-therapeutic period is required to identify several types of cells, which carry a risk for a disease progression and subsequent post-therapeutic relapse. Cancer stem cells (CSCs) are a subpopulation of tumor cells that can drive tumor initiation and can cause relapses. At the time point of tumor initiation, CSCs originate from either differentiated cells or adult tissue resident stem cells. Due to their importance, several biomarkers that characterize CSCs have been identified and correlated to diagnosis, therapy and prognosis. However, CSCs have been shown to display a high plasticity, which changes their phenotypic and functional appearance. Such changes are induced by chemo- and radiotherapeutics as well as senescent tumor cells, which cause alterations in the tumor microenvironment. Induction of senescence causes tumor shrinkage by modulating an anti-tumorigenic environment in which tumor cells undergo growth arrest and immune cells are attracted. Besides these positive effects after therapy, senescence can also have negative effects displayed post-therapeutically. These unfavorable effects can directly promote cancer stemness by increasing CSC plasticity phenotypes, by activating stemness pathways in non-CSCs, as well as by promoting senescence escape and subsequent activation of stemness pathways. At the end, all these effects can lead to tumor relapse and metastasis.