Cancer Stem Cells are a subpopulation of tumor cells that have undifferentiated properties like stem cells, producing the heterogeneous lineages of disease cells that contain the tumor.
Accordingly, Cancer Stem Cells (CSSs) must be characterized by their capacity to imitate the age of a constantly developing tumor. CSCs, also called tumor initiating cells have been seriously considered in the previous decade, concentrating on the potential source, origin, cell markers, study of mechanism, and advancement of therapeutic approaches targeting on their pathway.
Recent researches on cancer stem cells verified the presence of CSCs in particular diseases and molecular markers for isolation of cancer stem cells. Numerous years after the reasonable suggestion of the presence of stem-like cancer cells, experimental proof was first given in a leukemia model, affirming that CD34+ CD38− leukemic cells which indicated bone marrow hematopoietic undifferentiated cell properties.
Solid tumor cancer stem cells were first identified in breast carcinoma trailed in different types of cancer, including ovary, brain, colon, pancreas, lung, liver and prostate tumor.
Though, studies have demonstrated that cancer stem cells additionally add to the reconstitution of the microenvironment through trans differentiation into lineages which resemble common stroma, for example, endothelial cells of blood vessels, fibroblasts or pericytes.
Characteristics of Cancer Stem Cells
CSCs are a subdivision of cancer cells having the capacity to self-reestablish and initiate tumor development. Firstly, they were identified in acute myeloid leukemia in the late 1990s. Since then, CSCs have been identified in numerous solid tumors.
Within the most recent two decades, CSCs have turned into a subject of exceptional research as a potential focus for cancer therapeutics. The cancer stem cell field is generally new, and CSC targeting on therapeutics is in their initial stages. CSCs are at a less-differentiated state as compared to consistent cancer cells. Like other stem cells cancer stem cells have capability for asymmetrical /symmetrical division.
Cancer stem cells divide into two different daughter cells during asymmetrical division, one of which duplicates the mother cell’s whole genome, while alternate has less highlights of stemness. Because of their capacity to isolate asymmetrically, cancer stem cells have the limit with respect to tumor initiation and self-renewal.
These properties of uneven division and self-renewal enable cancer stem cells to sustain dynamic control of their numbers, and tumors constantly comprise of a mixture of CSCs and their differently differentiated progeny, adding to the phenotypic and functional heterogeneity of cancer stem cells.
Because of their self-renewal and tumor-initiating properties, CSCs are accepted to be the beginning stage for malignant growth and are thought to play significant role in cancer deterioration and metastasis. Thus, CSCs have turned into a promising focus for anticipating malignancy relapse and for infinitely enhancing the survival of cancer patients.
CSCs are regularly dormant and remain in the cancer stem cells specialty, which prevent them from damage by any of the prevailing anti-tumor treatments. The cancer stem cells niche is a favorable situation for CSCs to accomplish an ideal harmony between self-reestablishment, initiation and differentiation.
In light of stress, CSCs can be “enacted” and enlisted into different tissues, where they separate and produce tumor cells. Dormant cancer stem cells play a minor role in progressive malignant growths that have a poor reaction to treatment and that just “initiated” CSCs add to proliferation, development and therapeutic failures.
Accordingly these cells ought to be focused on and eradicated. Though, malignant growth cells in different states could stochastically travel among states and create a phenotypic balance in breast cancer.
Demonstrating that immortal, dormant cancer stem cells and even non-CSCs might travel into multiplying CSCs while multiplying CSCs are abolished.
Numerous undifferentiated cell particular markers and functional techniques have been utilized to distinguish putative CSCs for both in vitro and in vivo. Some CSC-related markers are being created as potential malignant growth treatment targets. Though, it remains testing to target CSCs as a result of their difficult biology and variability.
To date, no all-inclusive CSC marker for recognizing CSCs in all tumors has been distinguished. Moreover, cancer stem cells live in a CSC specialty, which may prevent their phenotypic versatility, prevent them from the immune system and keep up their dynamic number and state, in this way making it more complex to target them.
Cancer stem cells (CSCs) give rise to a differentiated progeny which contributes in the formation of tumors, CSCs initiated tumor growth. Patient’s prognosis is correlated to the gene expression files. CSCs are resistant towards radiation through damage repair.
Specific signaling pathways are linked with CSC differentiation. As the biological properties are being revealed, it is leading to the progress in CSC –targeted therapies for cancer treatment.
CSCs in Breast tumors:
The cancer in breast originates in the milk ducts or breast lobules. The common myo-epithelial layer in structures forms a basal layer whereas the ductal epithelial layer and alveolar synthesize milk in the lobules.
Breast cancers are of two types: Ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). In situ diagnosis of the cancer leads to highly effective therapeutic treatment. When the prognosis worsens the tumor invades the tissues it easily becomes metastatic; metastatic phase of this disease lead to the majority of deaths.
Breast cancer tumors reveal heterogeneity of two types such as different tumor subtypes as well as functional differences at cellular level.
Breast tumor subtypes vary in histopathology, molecular pathology, genetic composition and genetic expression which involve mutation in chromosomes and oncogene expression. Six breast cancer subtypes have been studied: luminal subtype A, B; HER2-overexpressing; normal breast like; basal-like and claudin low subtype. Tumor-initiating categories include cancer cells that propagate, maintain and have the ability of self –renewal whereas the second category is unable to produce large amounts of progeny.
The breast cancer stem cell arise from mutated normal tissue stem cells or from dedifferentiated mature cells that have the ability to grow besides tumorigenic mutations.
The aldehyde dehydrogenases (ALDH) are a contributor to cancer cells instability and can create mutations which are tumorigenic. The Aldefluor® assay thus used provides quantitative analysis of the functionality of ALDH and it is important tool used in studying the normal and cancer stem cells. ALDH has identified as functional marker of stem cells; it is common among all the cancer subtypes.
Breast cancer cells show resistance towards chemotherapy. CSCs are dormant and they retain the G0 phase, thus resisting the chemotherapy and radiation therapy. Clinically it has been noticed that after chemotherapeutic treatment CD44+CD24 increased in the breast cancer cells. The activity of ALDH metabolize cyclo-phosphophamide. The DNA repair mechanism and cell cycle checkpoints are two important factors which play an incentive role in radiation and chemotherapy resistance. The resistance may also be due to lower levels of pro-oxidants in CD44+ CD24.
Cancer Stem Cells in Prostate P-Ca:
The location of the P-Ca stem cells (PCSC) is in the prostate organ. In P-Ca CD133+ cells were observed to have a high proliferating potential. ALDH + P-Ca cells have self-renewal and tumorigenicity capacity. They also have increased expressions of CD44 as well as integrin α2β1.
Researcher are finding ways to target P-Ca non stem and progenitor cells with AR degradation enhancer ASC –J9® whereas P-Ca stem cells are treated with 5- azathioprine which resulted in the castration resistance in P-Ca cell lines in mice and human and lead to a better efficacy.
Cancer Stem Cells in brain tumor /glioblastoma
Glioblastoma is the most prevailing and fatal primary form of brain tumor. Glioblastoma multiforme (GBM), spreads easily in the brain surroundings and does not metastasizes to other body organs. GBM therapy focuses on surgical aid which is then followed by radiotherapy TMZ (temozolomide which is an oral methylation chemotherapeutic drugs).
GMB is characterized under genomic cancer types and has transcription related profiles which have been characterized such as classical, neural, proneural and mesenchyme. The genetics involve mutations in IDH1 and CpG island methyl phenotype CIMP which involves epigenetics. Single-cell RNA sequencing is used to cross-examine cell heterogeneity in GBMs recognized new genes present in GBM CSCs.
The differentiated and detected cells of multiple GBM subtypes are found within the single tumors, depicting the question of the utility of subtyping tumors and targeting specific subtypes.
GBM CSCs are present in various tumor microenvironment and exhibit the Warburg effect involving metabolic shift which leads to aerobic glycosylation and lactate accumulation. Glioma CSCs may shift towards the use of the pentose phosphate shunt in the restrictions of metabolic pathways.
Cancer Stem Cells in melanoma cancer
Melanoma CSCs have been confirm in the expression of markers including; CD34, CD271, CD44, ALDH1, CD271, JARID1 but all of these haven’t really shown that they are CSC specific. Transcription factors such as Nanog, oct3/4 are expressed in melanosphere which are related to melanoma cell lines. Cell surface marker of normal B cells CD20 has been involved in melanoma increase.
Identification markers of Solid tumors
Tumor markers are defined as molecules that identify the existence of cancer or may identify the future behavior of cancer in response to therapy, they also help in differentiation of benign and malignant tumors in asymptomatic patients.
Isolation of CSC biomarkers from total cancer cells is essential due to strong relationship between CSCs and process of tumor initiation, growth, development and drug resistance.
Identification of CSCs is currently being done by using fluorescence-activated cell sorting (FACS) depending on intra-cellular molecules or cell surface markers. Researcehrs identified a cell, termed brain tumor stem cell (BTSC), which was purified from human brain tumors and had the capability for proliferation, self-renewal and differentiation. Identification of this cell was possible by the expression of CD133 surface marker; normal neural stem cells also express CD133 and nestin.
Prostrate-specific antigen (PSA)
Prostrate-specific antigen (PSA) is a broadly used marker for analysis of prostate cancer, which first isolated from human seminal plasma as a first potential marker for investigation of rape crimes. It is a 33Kda serine protease, secreted by prostatic epithelial lining and has a role in liquefaction of seminal coagulum which aids in production of spermatozoa.
Before the PSA was known, another marker prostatic acid phosphate (PAP) was used but its low screening in advanced disease prevented its use for screening of prostate. PSA was found to have improved sensitivity over PAP, however, neither PSA nor PAP is considered as a specific marker since both of them may be elevated in benign prostatic hyperplasia.
Conclusion and Future Perspectives
Emerging remedial systems to target CSCs are important considering its effect on malignancy progression and diagnosis patients. Though, targeted removal of previous CSCs isn’t sufficient as many recent studies demonstrate that the CSCs can be generated from the differentiated non cancer stem cells.
CSC variety renders tumor impervious to counter malignancy treatments in the ultimately resulting in relapse, it is important to increase understanding from an exhaustive comprehension of CSC pliancy dependent on biology and molecular genetics.
The cancer stem cell field is a generally new one with a lot of research study still important to yield more significant towards better cancer treatment.
The CSCs theory offers another view for understanding tumorigenesis, and will probably prompt normal improvement of refined and novel treatments that yield substantial clinical advantages to patients. A significant body of evidence wires the theory that a sub populace of CSCs is related with a violent tumor phenotype described by expanded cell survival, replacement, intrusion, metastatic capability, treatment obstruction, and tumor relapse, all of which eventually contribute to poor diagnosis.
The distinguishing evidence of CSC-particular markers, and the isolation and classification of CSCs in tumor tissues will provide understandings that will be of an incentive in structuring methodologies for the improvement of chemotherapeutics that are required to lessen tumor aggression.
To progress cancer stem cell research, we have to initially comprehend the complex pathways that can control the stem cell properties. For this, discovery of cell surface particles for imminent isolation of stem cell and biologically related stem cell techniques are fundamental.
Eventually, with further upgrades in our comprehension of CSC, we will have the ability to grow better symptomatic therapeutic strategies, with which to classify, treat, and cure malignant cancer.
This article is jointly written by: Roeha Akhtar, Samra Javed, and Syeda Itrat Zahra Naqvi