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 Table of Contents  
REVIEW
Year : 2016  |  Volume : 2  |  Issue : 5  |  Page : 147-153

The molecular mechanism and regulatory pathways of cancer stem cells


1 Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
2 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
3 Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
4 Cipher Ground, 675 Rt 1 South, North Brunswick, NJ, USA
5 Department of Administrative, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
6 Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

Date of Submission06-Sep-2016
Date of Acceptance18-Oct-2016
Date of Web Publication24-Oct-2016

Correspondence Address:
Dr. Yanyang Tu
Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Xi'an 710038, Shaanxi, China

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2395-3977.192932

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  Abstract 

Malignant cancer is among the top of the life-threatening conditions, challenging humanity for a long time. Traditional methods of cancer therapy include surgery, chemotherapy, and radiotherapy, which aim to remove/destroy cancer cells. Although theoretically very promising, none of these methods can effectively eradicate cancer, the reason for which can be attributed to our incomplete understanding of the mechanism of cancer metastasis and recurrence. In recent years, researchers have proposed the theory of cancer stem cell (CSC). CSC is a small population of tumor cells that have unlimited self-renewal ability, exhibit a strong resistance to chemotherapy and radiotherapy, and have been proved to be the core reason of cancer metastasis and recurrence. CSC theory provides a deep insight into malignant tumorigenesis that brings new hope for tumor therapy. In this paper, we intend to discuss the development of CSC theory and summarize the regulatory pathways involved in CSC origin and self-renewal, which might be of assistance in the future development of malignant cancer therapy.

Keywords: Cancer stem-like cell, malignant tumor, regulatory pathway, surface maker


How to cite this article:
Wang Z, Yang H, Wang X, Wang L, Cheng Y, Zhang Y, Tu Y. The molecular mechanism and regulatory pathways of cancer stem cells. Cancer Transl Med 2016;2:147-53

How to cite this URL:
Wang Z, Yang H, Wang X, Wang L, Cheng Y, Zhang Y, Tu Y. The molecular mechanism and regulatory pathways of cancer stem cells. Cancer Transl Med [serial online] 2016 [cited 2019 Dec 9];2:147-53. Available from: http://www.cancertm.com/text.asp?2016/2/5/147/192932


  Introduction Top


Malignant tumor is one of the major threats the people are facing today. Recurrence and metastasis of malignant tumor are one of the leading causes of cancer patients' death and a major challenge in cancer treatment. Although biotechnology helps us to deepen the understanding of cancer, the primary cause of tumorigenesis, recurrence, and metastasis is still not clear. It has been observed that a subset of cancer cells exhibits self-renewal and differentiation abilities, just like stem cells, making the researchers put forward "cancer stem cell (CSC) theory." The theory proposes these CSCs to be the primary cause of tumor recurrence and metastasis despite the cancer therapy.

CSCs, also called tumor-initiating cells, are a small population of tumor cells that self-renew, like regular stem cells, and are capable of inducing tumorigenesis.[1] CSCs were first recognized in leukemia. An acute myelocytic leukemia (AML)-initiating cell was identified by transplanting AML cancer cells into severe combined immunodeficient (SCID) mice. The cells were then fractionated on the basis of cell surface markers and found that the leukemia-initiating cells, which could engraft within SCID mice to produce large number of colony-forming progenitors, were CD34+/CD38 . This in vivo model replicates many aspects of human AML and defines a new leukemia-initiating cell which was less mature than colony-forming cells.[2] From then on, CSCs were identified in many types of solid tumors such as breast,[3] brain,[4] colon,[5] lung,[6] and other tissues.[7] Meanwhile, the existence of brain tumor stem-like cells has been demonstrated in many patient tissues by several independent reports.[4],[8],[9],[10],[11] CSCs are demonstrated to be responsible for resistance to chemotherapy and radiotherapy, and induction of tumor angiogenesis and tumorigenic capacity, under hypoxiccondition.[12],[13],[14],[15] Majority of cancer cells in a primary tumor may be destroyed by chemotherapy and/or radiotherapy, but the resistive CSCs may regrow, resulting in cancer recurrence [Figure 1]. Hence, CSCs are considered to be the potential therapeutic targets in many types of cancers, for the accomplishment of which the critical molecular mechanisms regarding the maintenance of the CSCs "stemness" need to be understood. The available evidence suggests that CSCs are regulated by multiple factors including few signaling pathways, epigenetic-like microRNA, and tumor microenvironment, which will be introduced below, respectively.
Figure 1. Normal tissues arise from a central stem cell that grows and differentiates to create progenitor and mature cell populations. Cancer stem cells arise by means of a mutation in normal stem cells or progenitor cells and subsequently grow and differentiate to create primary tumors. Like normal stem cells, cancer stem cells can self-renew, give rise to heterogeneous populations of daughter cells, and proliferate extensively to form tumor at the end. During chemotherapy and radiotherapy, the majority of cells in a primary tumor may be destroyed; however, if the cancer stem cells are not eradicated, the tumor may regrow and cause a relapse

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  Molecular Markers of Cancer Stem-Like Cells Top


Almost every type of CSC and the tumor it forms has its own specific surface markers, the accurate detection of which is an important approach for effective cancer treatment. For a long time till now, many researchers have been committed to seeking tumor stem cell surface markers, the initial study of which was in blood system tumor; CD34+/CD38 phenotype of AML cells was first reported by Lapidot et al.[2] CD34+/CD38 phenotype cells isolated from AML patients could induce leukemia, similar to human, in mice, but lacked the ability to form tumors. Later, CD96+ was considered as an AML stem cell specificity marker as human CD45+ cells were found in CD96+ subsets in mice while not in CD96 subsets.[16] CD133+ and nestin were confirmed to be brain tumor stem cell surface markers.[17] Recent studies have classified CD44, CD133, CD166, and EpCAM as colon cancer CSC surface markers.[18] Lin-ESZ+ CD44+ CD24/low and ALDH1+ were reported as breast CSC surface markers.[19],[20] Zhou et al.[21] suggested CD133+ as one of the symbols of larynx CSCs, and the latest study suggested ALDH1 as one of the specific markers of the head and neck CSCs.[20] Fang et al.[22] confirmed that CD20+ fraction of melanoma cells was enriched with a subgroup of stem cell-like tumorigenic cells, which was proposed to induce the occurrence of tumor. ABCG2, ALDH1, MCM2, SCA-1, and p63 were established as stem cell surface markers of retinoblastoma CSCs by Seigel et al.[23] Levina et al.[24] obtained CD133+ , CD117+ , and OCT4+ expressing CSCs from lung cancer tumors, surviving after chemotherapy and thus were regarded as lung CSC markers. Further, studies suggested CD44, CD24, ESA, and CD133+ as markers for pancreatic CSCs, CD44+/CD133+/α-2β1hi were for prostatic CSCs and CD133, CD90 for liver CSCs.[25],[26] The CSC surface markers of different cancer types are listed in [Table 1]. We believe that further research of tumor stem cell markers will offer great help in cancer diagnosis and therapy.{Table 1}


  Cancer Stem-Like Cell Microenvironment Top


CSC microenvironment plays a very important role in the process of the cell invasion and metastasis during tumorigenesis and tumor progression. CSC microenvironment is mainly composed of cell factors, mesenchymal cells, immune cells, blood vessels, and extracellular matrix. Several factors, including low oxygen, adjacent blood vessels, inflammatory reaction, and epithelial-mesenchymal transition (EMT), collaboratively regulate CSC microenvironment.[27]

Hypoxic state is one of the influencing factors of the CSC microenvironment. Studies have shown that the adaptive response of CSC is regulated by hypoxia-inducible factors (HIFs), Oct4, c-Myc, and notch are the direct or indirect target of HIF.[28] In addition, HIF also regulates the process of CSC phenotype formation.[28] Regulating oxidative stress, within CSC microenvironment, has shown therapeutic effect in chronic myelogenous leukemia condition.[29] CSCs are closely associated with blood vessels, with respect to both position and function.[30] Inhibiting the NO effect and tumor angiogenesis, destroying the tumor blood vessels, and thus altering the vascular microenvironment adjacent to tumor stem cells can induce antitumor effect and regulate CSCs, indicating that adjacent vascular microenvironment is a CSC regulator.[30],[31] A variety of inflammatory factors, such as IL-6, IL-8, TNF-α, and MFG, are secreted into CSC microenvironment by mesenchymal cells and immune cells, which can regulate CSC by activating NFκB, Stat3, Hedgehog (Hh), and notch signaling pathways.[32],[33] These inflammatory factors can be used as targets to change the CSC microenvironment and thus alter the course of the condition.


  Cancer Stem-Like Cell Regulation Mechanism Top


Wnt pathway

Wnt signaling pathway controls embryonic development in both vertebrate and invertebrate animal and plays a vital role in the self-renewal of various adult (retinal, intestinal, breast tissue, and others) and embryonic stem cells.[34],[35],[36],[37],[38] Wnt/β-catenin signaling pathway plays a key role in the process of proliferation and differentiation of normal stem cells.[39],[40] In recent years, mutation in Wnt signaling pathway has been identified in several cancer types including colorectal cancer, hepatocellular carcinoma, pancreatic cancer, endometrial cancer, ovarian cancer, thyroid cancer, prostate cancer, and kidney tumor, indicating the regulatory role of Wnt signaling pathway in tumorigenesis. Consequently, the importance of Wnt pathway in CSCs also attracts much attention. Studies have shown that molecules such as Wnt-1 and β-catenin are overexpressed in some cancer cell lines such as the rat 4T1 breast cancer cell line and NXS2 neuroblastoma cell line.[41],[42] Excessive activation of Wnt signaling in normal stem cells results in their excessive proliferation and further leads to transformation of these stem cells into CSCs.[37],[38] Wnt signaling pathway is not involved in stem cell differentiation, as it is found suppressed in differentiating cells, and thus fails to activate the key downstream molecule β-catenin.[43] These studies indicate that the Wnt signaling pathway plays an important role in the fate of the CSC.

Notch pathway

Notch signaling pathway plays an important role in the normal stem cells' proliferation, differentiation, apoptosis, and intercellular communication.[44] Notch signaling pathway was first found in the genetic study of fruit flies as some allele of notch induced incision wings (mutant) (notched wings).[45] Notch pathway is essential in cell proliferation, apoptosis, nervous system development, and organs formation in both vertebrates and invertebrates.[46] Furthermore, notch signaling pathway is confirmed to be pivotal during tumorigenesis. Some notch signal-related molecules are found overexpressed in normal stem cells, reminding us that notch signaling pathway is closely connected with stem cell self-renewal.[47],[48] Studies have shown that the activation of notch signaling accelerates proliferation of neural stem cell, pituitary gland stem cell, and breast stem cell while also facilitates the formation of breast cancer microspheres.[49] However, other studies have shown that the activated notch signals can prevent excessive stem cell proliferation and protect them from malignant transformation.[50],[51]

Notch signaling pathway is closely related to the CSCs. Studies has shown notch-1 overexpression in MCF-7 breast cancer cell line, while its target gene Hes1 is higher in subsets of medulloblastoma. Inhibition of notch signaling leads to the deletion of medulloblastoma neural subgroup. However, overexpression of notch-2 cell structure domain causes great increase of the subgroup portion.[51] Apoptosis analysis shows that the inhibition of the notch signaling significantly increases the CSC apoptosis rate, without affecting the differentiated cells. Animal experiments reveal that the inhibition of notch signaling decreases tumorigenicity of cancer cells.[52] Regarding malignant tumor transformation, the notch signaling has been found to promote the transformation during tumorigenesis in few tissues while inhibiting the same in few other tissues.[53],[54],[55] Thus, as it seems, the regulation of CSCs' self-renewal and differentiation by notch signaling are tissue specific, the molecule mechanism of which needs to be further researched.

Hedgehog signaling

The secreted Hh proteins, encoded by Hh gene, regulate cell proliferation, differentiation, morphology, autocrine, and paracrine pathways. There are three known Hh signaling pathways: Desert, Indian, and Sonic. Abnormal Hh signaling is found in breast cancer, pancreatic cancer, prostate cancer, and other tumor tissues.[56] Hh signaling is a classic stem cell regulation pathway: Hh signaling pathway is found in Drosophila ovary stem cells, primitive hematopoietic stem cells, the intestinal progenitor cells, and mammary stem cells. In addition, Hh signaling also plays an important role in self-renewal of a variety of stem cells. A study demonstrated that the activation of Sonic Hh (Shh) receptor promotes the proliferation of human epidermal stem cells, while the addition of Shh inhibitor inhibited the proliferation.[57] In neuronal tissue, deletion of Shh leads to the neuronal microsphere damage; however, constitutive activation of Shh and c-Myc promotes the proliferation of neural progenitor cells and forms medulloblastoma.[58] The above points suggest that the Hh signaling pathway is of great importance in CSC regulation.

Janus family kinases/signal transducers and activators of transcription pathway

Recent work has demonstrated that Janus family kinases (JAKs) and signal transducers and activators of transcription (STATs) are important in the stimulus-response coupling of receptors lacking intrinsic tyrosine kinase activity. In particular, the JAK-STAT pathway appears critical in signal transduction by interacting with members of the hematopoietin receptor superfamily. Receptor tyrosine kinases, such as epidermal growth factor, platelet-derived growth factor, and colony stimulating factor-1, have been shown to induce increase in phosphorylation of both JAKs and STATs.[59] Without JAK-STAT signaling, germline stem cells (GSCs) can differentiate but cannot self-renew. Conversely, ectopic JAK-STAT signaling greatly expands both stem cell populations.[60],[61] JAK-STAT signaling from the hub acts on both GSCs and somatic cyst stem cells (CySC) to regulate their development and differentiation, and that additional signaling from CySCs to the GSCs plays a dominant role in controlling GSC maintenance during niche formation.[62] The JAK/STAT pathway has been shown to regulate stem cells during hematopoiesis and gametogenesis in Drosophila.[63]

Abnormal expression of transcription factor

Abnormal expression of transcription factors is essential for CSCs proliferation and self-renewal as many transcription factors are closely related with CSCs. The expression level of transcription factors such as Sox-2, c-Myc, Klf4, Oct4, and Lin28 are associated with CSC self-renewal and multidirectional differentiation abilities. Studies have found that these transcription factors are overexpressed in many human tumor tissues, and the level of expression is closely associated with the tumor progression and prognosis.[30] Abnormal expression of Oct-4 and NANOG is relevant with lung CSC self-renewal and EMT.[64] Transcription factors Twist and Zeb are also found involved in breast cancer EMT process, providing the tumor cells with stem cell-like properties.[65] All these transcription factors significantly contribute to CSC regulation, making it hard to justify the importance of a single factor.

MicroRNA

MicroRNAs regulate gene expression at posttranscriptional level. MicroRNAs play pivotal role not only in biological processes, including cell proliferation, differentiation, development, senescence, and apoptosis, but also in tumor formation, growth, differentiation, and progression.[66],[67],[68] Although multiple genes can be regulated by a single microRNA and several different microRNAs may have the same target mRNA, the regulation could be very precise through various arrangement and combination.[69],[70]

Studies have shown that the transcription factors in EMT such as Twist1, Snail1, Zeb1, and Zeb2 are regulated by microRNAs, and hence, microRNAs are regarded as EMT regulation factors.[71] Reports have shown that the miR-200 microRNA family can regulate the EMT process.[72],[73],[74],[75] miR-200-a/b/c, miR-141, and other members of the miR-200 family inhibit the expression of Zeb1 and Zeb2, during EMT, thus inhibiting the EMT while maintaining the epithelial phenotype of the cells.[74] In addition to the miR-200 family, miR-29b and miR-30 can regulate the EMT process. mir-29b, when overexpressed, can reverse the process of EMT, inhibiting the cell invasiveness.[76] miR-30 can regulate the expression of Snail1, suppressing TGF-β activity, which is required in inducing EMT.[77] Cell connection, which is the important initial step of EMT, can be weakened by miR-661 and miR-491-5p.[78] Thus, microRNAs are important in tumor cell EMT process.

MicroRNAs are reported to be involved in regulating embryonic stem cells, adult stem cells, and CSCs. MicroRNA plays an important role in normal embryonic stem cells self-renewal and differentiation ability.[79] miR-290 clusters, including miR-291-3p, miR-294, and miR-295, can enhance stem cell cycle through enhanced KLF4, OCT4, and SOX2 activity, thus rendering the cell pluripotent in the absence of c-Myc.[80] Studies show that the expression of miR-145 is decreased or increased in self-renewing or differentiating embryonic stem cells, respectively.[81] OCT4, SOX2, and KLF4 are direct target genes of miR-145, the high expression of which represses the pluripotency of human embryonic stem cells while inducing the lineage-restricted differentiation.[82] A study also shows that the overexpression of let-7 inhibits tumor formation and metastasis in NOD/SCID mice.[83] These findings suggest that the microRNAs are essential for maintaining CSCs stemness and regulating their differentiation, thus making the research in this field of microRNA very important in the field of cancer clinical therapy.

Epigenetic regulation

The molecular mechanisms of epigenetics include DNA methylation, RNA interference, histone modification, and chromatin remodeling.[84],[85] CSC may arise from normal stem cell/progenitor cells or from reprogrammed differentiated cells. Epigenetics plays important role in stem cell development and somatic cell reprogramming, hinting at its importance in CSCs occurrence and development.[86],[87],[88] Anomaly in signal transduction pathway and abnormal expression of transcription factors, caused by epigenetics, often appear in CSCs, resulting in a series of genetic changes. Pellacani et al.[89] found that the CD133-positive prostate CSCs are dynamically regulated by condensed chromatin. DNA methylation agent 5-Aza-Dc and histone acetylation inhibitors SAHA can inhibit notch signaling pathway of pancreatic CSCs through miR-34, thus inhibiting the CSC self-renewal and proliferation, reducing EMT and level of invasion.[90] The mechanism and method of epigenetics have been applied in the prevention, diagnosis, and therapy of tumors. Methylation-specific polymerase chain reaction has been applied to patient's body fluids and for living cells methylation-expression detection. It will be a powerful tool in tumor diagnosis. Future studies on the regulatory pathways of CSCs epigenetics and its function in tumorigenesis will provide great help to future cancer therapy.


  Conclusion Top


CSC theory provides new understanding and approach toward the tumor malignancy. CSCs are different from differentiated tumor cells, in the fact that the prior possesses stronger self-renewal ability and can get resistant to radiation and chemotherapy, ensuring their survival even after intensive chemo/radio-therapy. CSCs are believed to be the root cause of tumor recurrence and metastasis; hence, future studies on better understanding of their mechanism and regulatory pathways are important for the betterment of cancer therapies. This paper discusses the origin of CSCs, their surface markers, self-renewal abilities, and relative regulatory pathways. These mechanisms have far-reaching significance in developing targeted therapies for the elimination of CSCs and eventually eradicate cancers. However, the current research on CSCs is still at its infancy and more work is evidently needed for its better understanding. For example, only a few specific CSC markers have been found while more remains to be discovered. The molecular mechanism of drug resistance of CSCs against the known chemotherapies is still unknown and needs to be further researched. The core hub of contact signal transduction pathways and regulation pathways is not clear and some normal stem cells might also be killed during targeted therapy. Even though many issues of CSCs needs to be addressed, we believe that, with the continuous study of the mechanism of their regulatory pathways, new breakthrough in malignant tumor therapy will occur in the near future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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