Review Article

A Brief Review on Cancer Stem Cells

Satyanarayana Rentala1*, Animisha Mokkapati1, Radhakrishna Nagumantri1, Chinnababu Pydi1, Pavan Kumar Rambatla2, Donthamsetty Nageswara Rao3 and Aruna Lakshmi Komarraju2
1Department of Biotechnology, GITAM Institute of Technology, GITAM University, India
2Department of Biotechnology, GITAM Institute of Science, GITAM University, India
3Department of Biochemistry, GITAM Institute of Medical Sciences and Research, GITAM University, India


*Corresponding author: Satyanarayana Rentala, Department of Biotechnology, GITAM Institute of Technology, GITAM University, India


Published: 07 Sep, 2017
Cite this article as: Rentala S, Mokkapati A, Nagumantri R, Pydi C, Rambatla PK, Rao DN, et al. A Brief Review on Cancer Stem Cells. Ann Pharmacol Pharm. 2017; 2(18): 1095.

Abstract

More than a decade ago, the existence of a rare population with both stem cell-like properties and tumor initiating capability was first identified in acute myeloid leukemia and, subsequently, in several solid tumors. These populations with stem cell-like properties were termed ‘cancer stem cells (CSCs)’, indicating that only a subset of cancer cells were tumorigenic and able to initiate and produce the bulk of tumors, thus also termed ‘tumor initiating cells’. In this mini review on issues such as cancer stem cells markers, integrins, Matrix metallo-proteinases, chemokines and chemokine receptors are described to study the cancer stem cells associated metastasis. In this review article, several mechanisms and signaling pathways of cancer stem cells during self-renewal and differentiation were mentioned.
Keywords: Cancer stem cells; Matrix metallo-proteinases; Chemokines and integrins


Introduction

Many studies performed over the past 30 to 40 years, when viewed collectively, have shown that the characteristics of stem-cell systems, the specific stem-cell properties described above, or both, are relevant to some forms of human cancer [1]. A minor subpopulation of cells in tumor samples has the capacity to initiate clonal growth in in vitro cultures or in in vivo transplant models which has perplexed researchers in the past. Two theories were proposed to explain this paradox. The stochastic theory suggested that all cancer cells are equally malignant but only clones that randomly possess favorable biological properties will grow upon transplantation. An alternative theory predicted that tumors are hierarchical like normal tissues and only the rare subpopulation of cells at the pinnacle of that hierarchy have the unique biological properties necessary for tumor initiation. The role of stem cells is now being addressed in many solid tissue cancers. In 1990s Irving L. Weissman, coined these stem cells, “Cancer stem cell”, stem cells arising through the malignant transformation of adult stem cells. These cancer stem cells are proposed to be the source of some or all tumors and cause metastasis/relapse of the disease state. Biologically distinct and relatively rare populations of “tumor-initiating” cells have been identified in cancers of the hematopoietic system, brain, and breast [2]. Cells of this type have the capacity for self-renewal, the potential to develop into any cell in the overall tumor population, and the proliferative ability to drive continued expansion of the population of malignant cells as shown in Figure 1. The discovery of cancer stem cells implores the question regarding the origin of these cells. Are they derived from normal stem cells with a cancerous phenotype? Or do previously differentiated progenitor cells with oncogenic mutations regain the ability to self-renew? A third theory hypothesizes that CSCs may come from a rare fusion event between stem cells and other cells. Figure 2 indicates the possible origin of cancer stem cells [3-5].


Markers for Cancer Stem Cells

They represent a tumour cell subpopulation, own typical stem cell properties as self-renewal and potential to differentiate and are possibly responsible for tumour growth. We have a lack of knowledge about the cells equipment of molecular markers that can be used for isolation and purification. One of the already established markers is the transmembrane-protein CD133. The role of CD133 as tumor stem cells marker is well depicted in the following Figure 3. All tested cancer cell lines possess minor populations of cells with highest expression of CD133, CD44 and CD166, whereas many cells are CD133-negative [6-8]. Several experimental approaches indicated a higher proportion of CD133-positive cells with increased in vivo tumorigenicity and the ability to produce floating spheres. Markers expressed on normal and cancer stem cells are shown in Table 1.
The following proteins play important role during cancer stem cell mediated differentiation, migration and metastasis of many cancer types.


Integrins

The integrins are a super family of cell adhesion receptors that bind to extracellular matrix ligands, cell-surface ligands, and soluble ligands. Figure 4 shows the role of integrins in cell-cell communication. Integrins are transmembrane αβ heterodimers and till date at least 18 α and 8 β subunits are known in humans, generating 24 heterodimers as shown in Figure 5.


Matrix Metallo-Proteinases

The conventional wisdom of the role of Matrix Metallo-Proteinases (MMPs) during tumor development is that they facilitate degradation of key ECM components, thereby assisting invasion of tumor cells into ectopic tissue compartments. Recent insights into ECM function during remodeling processes, and identification of many non-matrix substrates for MMPs, have implicated these enzymes as regulators of the cellular microenvironment and cellular functions during normal development and neoplastic progression, e.g., cell attachment, migration, cell proliferation, differentiation, survival, genomic (in) stability, angiogenesis, and malignant potential. Significantly, MMPs are expressed mostly by stromal cells and inflammatory cells, but act on the epithelial cells to regulate infiltrating inflammatory cells, regulates ECM degradation, apoptosis, cell recruitment, proliferation, bioavailability of VEGF and angiogenesis, and thus co-ordinate numerous events in developing tumors. The list of MMPs and their information is give below in the Table 2.


Chemokines

Chemokines are a family of chemo attractant cytokines (small proteins secreted by cells that influence the immune system) which play a vital role in cell migration through venules from blood into tissue and vice versa, and in the induction of cell movement in response to a chemical (chemokine) gradient by a process known as chemotaxis. In addition, chemokines also regulate lymphoid organ development and T-cell differentiation, mediate tumour cell metastasis, and have recently been shown to have a function in the nervous system as neuromodulatorss. In order for a cell to respond to a chemokine it must express a complementary chemokine receptor. Chemokine receptors belong to the vast family of G-protein coupled receptors (GPCRs): seven transmembrane receptors which bind extracellular ligands and consequently initiate intracellular signalling. When a chemokine binds its receptor a calcium signalling cascade is created, resulting in the activation of small GTPases [8-10]. This then has downstream effects such as activation of integrins (molecules involved in cell adhesion) and actin polymerisation, resulting in the development of a pseudopod (cellular projection), polarised cell morphology and ultimately cell movement. Chemokines are grouped and named according to their amino acid composition, particularly on the first two cysteine residues of a conserved tetra-cysteine motif. The CC and CXC chemokines form the two largest groups [10-13]. The molecules CX3CL1, XCL1 and XCL2 are also regarded as chemokines. In fact, the molecules expressed on a cell determine which tissue a cell will migrate into. For example, cells expressing the chemokine receptor CCR7 migrate to lymph nodes, where their ligands, CCL19 and CCL21, are expressed. Chemokines also regulate angiogenesis in the tumor microenvironment. The N terminus of several CXC chemokines contains three amino acid residues [Glu-Leu-Arg (ELR motif)], which precede the first cysteine amino acid residue of the primary structure of these cytokines [14,15]. CXCR4 is by far the most common chemokine receptor that has been demonstrated to be over expressed in human cancers. More than 23 different human malignancies, including breast cancer, ovarian cancer, melanoma, and prostate cancer, express CXCR4 [16]. Although CXCR4 can be expressed in a broad array of tissues, CXCR4 expression is low or absent in many normal tissues, including breast [17] and ovary [18]. Its sole ligand, CXCL12 is constitutively produced in multiple tissues, including those where metastases develop frequently (i.e., lung, liver, and bone).
Despite the increasing number of studies on genes and pathways involved in cancer “stemness”, factors in the tumor microenvironment that regulate CSCs, and how cancer cells, in turn, modify the niche by influencing their neighboring cells remain largely uncharacterized. Fibroblasts release a variety of growth factors, chemokines, and components of the extracellular matrix into the microenvironment and influence the differentiation and homeostasis of adjacent epithelia. Cancer-associated fibroblasts (CAFs) can promote cancer progression by modulating multiple components in the cancer niche to build a permissive and supportive microenvironment for tumor growth and invasion. The chemokines and their CXC members are given below in Table 3.


Figure 1

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Figure 1
Asymmetric division in stem cells. (a) asymmetric division in a normal stem cell. a stem cell can self-renew to give rise to another stem cell (green) but can also divide to form a progenitor cell (pink). (b) asymmetric division in a cancer stem cell. a cancer stem cell (orange) can also asymmetrically divide to form another cancer stem cell (orange) or give rise to a progenitor cell (brown).

Figure 2

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Figure 2
Development of cancer stem cells from the normal stem cells and progenitor cells. Accumulation of DNA errors in normal stem cells or progenitor cells are activated to generate a cancer stem cells (CSCs) that further generate a primary tumor constituting CSCs and other tumor cells.

Figure 3

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Figure 3
Prostate cancer tissue derived CD133+ cells are involved in tumorigenesis in mouse models.

Figure 4

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Figure 4
Role of integrins in cell-cell communication.

Figure 5

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Figure 5
Classification of Integrins.

Table 1

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Table 1
Markers expressed in normal and cancer stem cells in humans.

Table 1

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Table 2
Description of matrix metallo-proteinases (MMPs).

Table 3

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Table 3
CXC and CC chemokine members.

Cancer Stem Cells Mediated Metastasis

Metastatic spread of cancer cells from the primary tumors to distant vital organs, such as lung, liver, brain, and bone, is responsible for the majority of cancer-related deaths [19]. Cancer stem cells are likely to play essential roles in the metastatic spread of primary tumors because of their self-renewal capability and their potential to give rise to differentiated progenies that can adapt to different target organ microenvironments [20]. Investigating the metastatic behavior of cancer stem cells (CSCs) is critical for the development of more effective therapies to prevent or delay the progression of malignant diseases.


Conclusion

Tumorigenic contribution of CSCs is still not fully uncovered. This is in part explained by the presence of heterogeneous population due to the lack of exact definition of CSC population. However, many evidences suggest that CSCs are actively recruited into tumor site, and contribute to tumor microenvironment as either themselves or as the tumor-associated fibroblasts. They directly or indirectly regulate tumor cell proliferation, differentiation, immune tolerance, angiogenesis, metastasis and drug resistance through the interaction with numerous cytokines and growth factors as well as providing niche to the cancer cells in cooperated with ECM. To study the above-mentioned list of the contents in cancer stem cells it is important to maintain a database. Such a database on cncer stem cells will surely help not only the researchers but also clinicians for the development of pharmacotherapeutics.


References

  1. Reya T, Morrison SJ, Clarke MF, Weissman IL. “Stem cells, cancer and cancer stem cells”. Nature. 2001;414(6859):105-11.
  2. K Moitra, H Lou, M Dean. “Multidrug Efflux Pumps and Cancer Stem Cells: Insights into Multidrug Resistance and Therapeutic Development”, Clinical Pharmacology & Therapeutics. Clin Pharmacol Ther. 2011;89(4):491-502.
  3. Bjerkvig R, Tysnes BB, Aboody KS, Najbauer J, Terzis AJ, et al. “The origin of the cancer stem cell: current controversies and new insights”. Nat Rev Cancer. 2005;5(11):899-904.
  4. Bonnet D, Dick JE. “Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell”. Nat Med. 1997;3(7):730-7.
  5. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF, “Prospective identification of tumorigenic breast cancer cells”. Proc Natl Acad Sci U S A. 2003;100(7):3983-8.
  6. Al-Hajj M, Clarke MF. “Self-renewal and solid tumor stem cells”, Oncogene, Oncogene. 2004;23(43):7274-82.
  7. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, et al. “Identification of pancreatic cancer stem cells”. Cancer Res. 2007;67(3):1030-7.
  8. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, et al. “Identification of a cancer stem cell in human brain tumors”. Cancer Res. 2003;63(18):5821-8.
  9. Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV, et al. “Direct isolation of human central nervous system stem cells”. Proc Natl Acad Sci USA. 2000;14720-5.
  10. Fang D, Nguyen TK, Leishear K, Finko R, Kulp AN, Hotz S, et al. “A tumorigenic subpopulation with stem cell properties in melanomas”. Cancer Res. 2005;65(20):9328-37.
  11. Klein WM, Wu BP, Zhao S, Wu H, Klein-Szanto AJ, Tahan SR. “Increased expression of stem cell markers in malignant melanoma”, Modern Pathology. Mod Pathol. 2007;20(1):102-7.
  12. Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, et al. “Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma”. Proc Natl Acad Sci U S A. 2007;104(3):973-8.
  13. Collins AT, Maitland NJ. “Prostate cancer stem cells”, Eur J Cancer. 2006;1213-1218.
  14. Strieter RM, Polverini PJ, Kunkel SL, Arenberg DA, Burdick MD, Kasper J, et al. The functional role of the ELR motif in CXC chemokinemediated angiogenesis. J Biol Chem. 1995;270:27348-27357.
  15. Balkwill F. Cancer and the chemokine network. Nat Rev Cancer. 2004;4(7):540-50.
  16. Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410(6824):50-6.
  17. Scotton CJ, Wilson JL, Milliken D, Stamp G, Balkwill FR. Epithelial cancer cell migration: a role for chemokine receptors? Cancer Res. Cancer Res. 2001;61(13):4961-5.
  18. Craft N, Shostak Y, Carey M, Sawyers CL. “A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase”. Nat Med. 1999;5(3):280-5.
  19. Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, et al. “Cancer  stem  cells:  perspectives  on  current  status and  future  directions: AACR Workshop  on Cancer Stem Cells”. Cancer Res. 2006;66(19):9339-44.
  20. Patrawala L, Calhoun-Davis T, Schneider-Broussard R, Tang DG. “Hierarchical organization of prostate cancer cells in xenograft tumors: the CD44+alpha2beta1+ cell population is enriched in tumor-initiating cells”. Cancer Res. 2007;67(14):6796-805.