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The hypothesis revolving around the Cancer Stem Cell (CSC) was originated in 90s in myeloid leukemia that was investigated by John Dick. The hypothesis based on the fact that tumors origin from a single cell has not been properly demonstrated using the CSC model mainly because CSC are not present in end stage of tumors. Origin hypothesis includes mutants in developing cells acquiring stem cells like attributes focusing more on tumor’s cell of origin. Evidences suggest the fact that cancer develops from tumor cells possessing stem cells characteristics termed as cancer stem cells. These cells resist to a number of cancer therapies and are also successful in passing the same resistance mechanism to other cells within the tumor (Kahn et al, 2015). Stem cells are further responsible for the growth of tumor, recurrence, and metastasis. A number of scholars found that malignant tumors are developed because of the rising population of tumor cells that share similar biologic attributes with general and normal stem cells. The hypothesis revolving around the Cancer Stem Cell (CSC) is based on analysing that tumors arise from the cells exhibiting the ability of self-renewal along with giving rise to differentiated tissue cells. A number of investigators postulated that cancer arises from the cells with stem cell properties (Redig and McAllister, 2013). Like the general stem cells, the CSC can also divide themselves in an indefinite manner resulting into more numbers of CSCs that also differentiates into the wide arrays of cell types in a tumor. They also maintain some of the properties of the tissue of origin and give rise to tumors that often resemble their origin either through the expression of tissue-specific genes or morphology (Beck and Blanpain, 2013).
The CSC hypothesis also raises a number of significant clinical and experimental implications. The first one is in the form, if the population of a biologically unique CSC exists, then there is every possibility that tumor cells lacking stem cells attributes will not be able to initiate tumors (Allison et al, 2010). Bozorgi et al (2015) stated that since the introduction of CSC theory, there have been significant developments in understanding cancer and the basic structure and formation of tumors. In 2003, the isolation of CSC from the first solid tumor in breast cancer suggested the fact that major reason behind the therapy failure was because of the presence of CSC. It leads to treatment resistance causing metastasis and recurrence. This means that the rise of complexities and resistance in breast cancer was majorly because of the presence of CSC that also justifies the CSC hypothesis based on mutants in developing cells acquiring stem cells like attributes focusing more on tumor’s cell of origin However, there are some differences and similarities in regards to CSC and non-cancer stem cells. One of the basic differences between the CSC and non-cancer stem cells is the element of dependency on stem cell niche and metastatic niche. It is a specialised microenvironment where the stem cells reside (Marcato, et al, 2015).
The niche of the stem cells in adult somatic tissue often plays an important and crucial role in maintaining stem cells or preventing them from the act of tumorigenesis by offering inhibitory signals for the purpose of differentiation and proliferation. In terms of the similarity, it can be said that CSC and non-cancer stem cells share similar attributes in terms of sharing the self-renewal feature that has also changed the perspective in regards to treating the disease in a significant manner (Beck and Blanpain, 2013). In this regard, Wnt and Notch pathways are assumed as important CSC regulators. In addition, molecule markers can be used to detect CSC in breast cancer but the same cannot be used in stem cells. It is also used to distinguish these two. A clear overview of the difference between the normal and cancer stem cells have been highlighted for better degree of understanding (Wicha et al, 2006).
| Normal Stem Cells | Cancer Stem Cells | |
|---|---|---|
| Definition | They are undifferentiated biological cells that can differentiate into specialised cells along with producing more stem cells. | Cancer stem cells are found in tumors and lead to multiple cell types found in a particular cancer |
| Impact | Normal stem cells does not form tumors | Cancer stem cells have the ability to form tumors |
| Quality | These cells maintain the normal turnover of regenerative organs | These cells lead to more such cells that lead to further deterioration of multiple organs. |
| Nature | Normal stem cells might turn into cancer stem cells | Cancer stem cells already generate tumors |
The discovery of CSC has affected the cancer biology community thinking, in terms of explaining the resistance of cancer to conventional therapies including chemo, radiotherapies, and drugs. The hypothesis states that CSCs are often marked with subpopulation within the tumor with specific and superior resistance and extraordinary ability to self-renew that initiates tumor in the short and long run (Macconaill and Garraway, 2010). In last few years, CSCs have gained tremendous interest in terms of initiating tumor development playing a crucial role in recurrence following the stringent chemotherapy. There are wide arrays of mechanisms of chemo resistance have been discussed in the past being identified as CSCs. Some of these mechanisms have been discussed as follow.
ABC Transporter and CSCs
It is often seen that the reoccurrence of tumors following chemotherapy is mainly because of the fact that few cells are left out from the chemotherapy. As CSC has been responsible for initiating tumors during recurrence, it is often believed that chemo-resistance mechanism is helpful in identifying CSCs. One such method is in the form of ATP Binding Cassette (ABC) transporters that are often considered as useful in isolating hematopoietic stem cell. They were also defined as side population (SP) cells. In one of the studies, it was found that SP cells were identified as the key tumor initiating CSCs. In addition, these cells were found to be repopulating both SP and non-SP cells signifying the self-renewal properties (Singh, et al, 2003).
This SP analysis has been widely used in regards to breast cancer and the presence of SP cells in in malignant tumors was very much driven by the genetic alterations of tumors. It was further found that CSCs in the form of SP cells showcase chemo-resistance related to the ABC transporter. In this regard, two ABC transporters in the form of P-glycoprotein (MDR1) and breast cancer resistance protein (ABCG2) were found to be mediating the SP cells in CSCs as well as in the normal cells. ABC transporters that mediate the SP phenotype can be overcome using mechanism of chemo resistance involving the use of different inhibitors related to ABC transporters (Wicha and Dontu, 2006). ABC transporters include a number of subunits and few of them are transmembrane protein while few are also membrane associated ATPases. These ATPase subunits consume energy of adenosine triphosphate (ATP) binding to energies the translocation of a various substrates in different membranes through export of the substrate or for uptake.
Aldehyde Dehydrogenase Related Chemo-resistance
Aldehyde dehydrogenases (ALDHs) are assumed as quite important in terms of maintaining and differentiating the stem cells and other cells development. There is also growing reputation for ALDH expression promoting chemo-resistance along with leading to survival mechanisms in CSCs (Vasiliou and Nebert, 2005). It was further found that members of ALDH family of proteins include a new class in regards to the potential targets. Human bodies have around 19 ALDH proteins that many of them are possessing cancer related functions. In regards to breast cancer, it was found that the major problem was in the form of recurrence and relapse after radiotherapy. It was found that because of the ALDH proteins, there was radiation resistance in terms of treating patients with breast cancer. They were also found to be having greater ability of increasing the frequency of cells initiating tumors (Singh, et al, 2003). ALDH proteins are found to be radiation resistance and tumor recurrence mainly in breast cancer. They also form, spheres and colonies with greater frequency of tumor initiating cells. ALDH also promotes CSC phenotype through enhanced DNA repair.
Role of CSC-related Signaling Pathways in Chemo-resistance
Many scholars believed that signaling pathways contribute to the CSC biology including chemo-resistance. The WNT/β-catenin signaling pathway is one such pathways helping in CSC renewal in wide arrays of cells and also in normal stem cells. In few of the studies, it was found that there was a possibility of chemical activation in regards to WNT pathway that facilitated the renewal of OV6_hepatic CSCs where the β-catenin led to self-renewal. These mechanisms also exhibited enhanced degree of chemo-resistance.
It was further found that these WNT pathways mediate through the up regulation of ABC transporter pumps. There are also a number of other signaling pathways that leads to chemo-resistance in CSCs but are dependent on the origination of cells and other genetic alteration that leads to the formation of CSCs (Allison et al, 2010).
Altered DNA Damage Response in CSCs
A major and important mechanism contributing in the growth of cancer and further resistance towards radiation and drugs is in the form of DNA damage response. It can be said that during the hypoxic condition, tumor cells can result into the DNA damage through hypoxia inducible factor transcription (Kahn et al, 2015). After the detection of hypoxia and gaining response to the DNA damage, low signal pathways are activated in the form of ATM and Rad-3-related (ATR) and ataxia telangiectasia mutated (ATM). The activation of these signals impairs the cell division cycle in a negative manner that leads to wide arrays of resistance (Meng, et al, 2014).
Based on the discussion, it can be said that CSCs can escape the detrimental and ill effects of chemotherapy, radiotherapy, and drug effects through a number of mechanisms. Even though, few of the mechanisms have been discussed, there are a number of other mechanisms through which CSCs mediates chemo-resistance in breast cancer. However, identifying the appropriate CSCs in regards to breast cancer is important in overcoming the drug treatment failures along with enhancing the impact and effects of chemo and radio therapy on patients undergoing treatment for the same.
There are a number of strategies that are used to target CSC population both in the clinical and laboratory settings. Some of the key therapies and strategies being used have been discussed as follow. The below picture states the thereupatic strategies that have been further elaborated.
Reference: Kim, Y., Siegler, E., Siriwon, N., & Wang, P. (2016). Therapeutic strategies for targeting cancer stem cells
Regulating CSC Regulating Pathways
Ali et al (2011) stated that many pathways are often deregulated in CSC. They are also probable targets in anti CSC therapeutic initiatives. Furthermore, Notch pathway has been widely used in CSCs by impacting the EMT and contributing towards the invasiveness of the CSCs. Further findings suggested that there is a effect of psoralidin that is a bioactive compound on Notch signaling in the breast cancer model. This plant-derived drug inhibits the Notch signals in CSCs especially in breast cancer and other forms of cancer. It also helps in decreasing the mammosphere formation and further proliferation of CSC in a critical manner. Further findings suggested that Hedgehog signaling pathway also contribute to the CSC formation and inhibit the proliferation of CSCs. Several studies also suggested that Hedgehog signaling is also associated with Wnt pathway and different small molecule antagonists of Wnt reduces the mammosphere formation to an extent even though, the findings are at preliminary stages. (Campbell and Copland, 2015).
Silencing Oncogenes
Duan et al (2013) reported that RNAi is a biological process where mRNA are targeted by small interfering RNAs to degrade and thus affecting the growth of the gene. They are used to deliver the RNA to the point of action within the target gene area and avoiding off target gene area. The use of lentiviral short hairpin RNA (shRNA) is used to inhibit the growth of human papilloma virus gene E6 in CSC enriched cancers. After the exposure of shRNA, the growth and formation of CSC was significantly reduced and inhibited. The silencing of E6 often led to a decrease in CSC. It was measured using HPV pseudovirions coding sequence increasing the efficacy of RNA. Greve et al (2012) suggested that the validity, reliability, and application of RNAi in clinical settings have been affected by the inability of delivering high strength to the site affected by tumor. The use of PEGylated EpCAM aptamers in guiding the siRNA to EpCAM over expressing CSCs was useful in knocking down the surviving gene. It was also found that when combined with doxorubicin, the aptamer siRNA helped in improving the survival rates of people suffering from tumors in breast, stomach, and cervix. In vivo and in vitro also suggests the effectiveness of anti CSC RNAi (Ali, et al, 2011).
Targeting CSC Surface Markers
Gu et al (2011) mentioned other therapeutic approach that can target the surface markers of CSC. One such biomarkers that is quite efficient is in the form of CD44 that is also a cell surface matrix receptor. A number of studies have further highlighted CD44 antibody therapy to be used in the anti CSC approach (Duan et al, 2013). Majority of the cancer cells show resistance towards chemotherapy and radiotherapy but when AC133 antibody was integrated to the powerful cytotoxic drug mono methyl auristatin, it showed higher degree of effectiveness against cancerous cells (Minn et al, 2005). It is a marker that is found on multipotent progenitor cells. It can be further said that the humanised EpCAM antibodies are quite relevant and conclusive in clinical and preclinical studies showcasing potent and anti-tumor activities. Quantitative flow cytometric analysis in regards to gastric and pancreatic cancer was used (Smith et al, 2008).
Inhibiting ABC Transporters
There is no doubt that the CSC chemoresistance is mainly because of the ABC transporters. However, there are a number of pharmacological and agents that showcase neutralising effects on these transporters (Minn et al, 2005). Even though, there are three major inhibitors of ABC transporter and p-gp inhibitor Vardenafil has shown great deal of promise in terms of mitigating the effects of P-gp over expression. It was further found that Verdenafil blocks the P-gp mediated drug efflux that further leads to an increase into the concentration of cytotoxicity and vincristine. Wang et al (2012) further added that nanotechnology is either used in combination or alone and both have great deal of benefits. There is no doubt that P-gp can be easily surpassed using siRNA loaded dextran polymeric nanoparticles. This often helps in enhancing the resistance towards CSCs in a critical manner.
Enhancing Immune Responses
Duan et al (2013) added that immunotherapy has evolved as highly significant treatment for cancer patients including metastatic cancer. There are a number of strategies that can enhance the immunity of patients and one of them is in the form of immunomodulation activating the immunity response and cell transfer of ex vivo-expanded lymphocytes like natural killer cells. There are also non-specific immunomodulation including the use of FDA approved cytokines like IFNα and IL-2.
In terms of the experiment being conducted on animals, it was found that the use of high dose of IL-2 reduced the lung and liver metastases and in terms of human beings, it was found that the clinical response was around 15-20%. This means that the response is significant in terms of enhancing the immunity to overcome CSC issues (Wang et al, 2013). Another strategy is in the form of adoptive transfer of chimeric antigen receptor (CAR) T Cells that can target any cancer antigens having high binding affinity. There are also pre-clinical models suggesting the fact that CARs can be used to target CSCs along with inhibiting the growth of metastatic cancers including breast cancer.
Targeting the Tumor Microenvironment
There are three major attributes of CSC microenvironment in the form of hypoxia, perivascular niche regulating the capacity of proliferation, and secretion of inflammatory cytokines. The microenvironment of tumor is also explored as pharmaceutical target of CSCs. It was further found that blocking of IL-6 signaling can decrease the tumor growth and size along with enhancing the resistance towards chemotherapy. However, the effect and impact of blocking single cytokine is quite limited as IL-6 is critical for the growth of xenograft tumor and combined expression of these genes leads to poor prognosis in patients suffering from breast cancer. Thus, it is important to inhibit IL-6 as well as IL-8 to affect the tumor growth in a negative manner (Ali et al, 2011). Another way of attacking CSC niche is in the form of tumor hypoxia that activates the hypoxia inducible factor pathway along with up regulating HIF-1α that mediates numerous effects of hypoxia in wide arrays of tissues along with increasing the resistance towards chemotherapy and radiation in a significant manner.
Nano Medicine in Combination Therapy
CSC targeted therapeutic agents are formulated over a period of time and some of them include thioridazine, hydrochloride, miR-34a, salinomycin, and curcumin. There is no doubt that in spite of carrying clinical significance and evidences, there clinical application has been majorly affected by the hydrophobicity and poor specifity (Gu et al, 2011).
However, there have been development in nanoparticle delivery in the form of new strategies that have potential to deliver therapeutic in overcoming the challenges posed by CSCs along with improving the overall therapeutic efficacy by improving bio distribution and prolonging the circulation time (Greve et al, 2012). The nanoparticle drug treatment targets CSC population in tumor. It can be further said that only using CSC inhibitor might not be fully effective in thwarting the progress of tumor. This is generally because of the lack of cytotoxic nature compared to conventional chemotherapeutics.
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