How can stem cells help with cancer treatment?
Cancer is considered to be one of the most challenging diseases. There are several cancer treatments available, such as surgery, radiotherapy, chemotherapy, and immunotherapy, but they often result in suboptimal efficacy, therapy resistance, and tumour recurrence [1,2]. Stem cells possess unique characteristics, including self-renewal and high-capacity of differentiation. Stem cells have been widely studied and can be roughly categorised into several groups: embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), and cancer stem cells (CSCs). Recently, stem cells are shown to have the potential to improve cancer treatment by regenerating cells after heavy therapy, targeting cancer pathways, generating immune cells, and being therapeutic carriers (Figure 1) [3].
Stem cell transplantation
Hematopoietic stem cells (HSCs), located in bone marrow, can form all mature blood cells in the body. High-dose radiotherapy or chemotherapy not only has effects on cancer cells but also normal cells, causing slow cell growth or even cell death [4]. HSC transplantation is now a standard treatment used in multiple myeloma, leukemia, and lymphomas targets after rounds of therapy to help patients recover. For example, in Leukemia patients, HSCs are infused to help proliferate and differentiate into new blood cells by adding colony-stimulating factors, which activate intracellular signaling pathways in HSCs [5]. Till now, the infusion of HSCs is the only procedure of stem cells that was approved by the FDA. However, the occurrence of graft-versus-host-disease (GVHD) when using allogeneic sources of HSCs remains a challenge, which is often treated with immunosuppressive drugs [6-8].
Targeting CSC pathways for cancer therapy
Cancer stem cells (CSCs) were first identified in leukemia in 1994. These cells are generated by epigenetic mutations in normal stem cells or in precursor/progenitor cells and found within tumour tissues. The failure of cancer treatment could be attributed to the characteristics of CSCs. They can generate tumours via self-renewal and differentiation into multiple cellular subtypes as normal stem cells. Although the proportion of CSCs in tumour tissues is very low, they contribute to multiple tumour malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance [9]. The surface markers, such as CD166, CD44, Endoglin/CD105, HER2/ERBB2, Lgr5, and EpCAM, are often used to identify CSCs from highly heterogeneous cell types in tumors [10]. The activities of CSCs are regulated by pluripotent transcription factors, many intracellular signal pathways, and extracellular factors, and these factors can be used as drug targets for cancer treatment. Therefore, targeting CSCs could provide a promise to treat various types of solid tumours.
Stem cell source for production of immune cells
Chimeric antigen receptor (CAR) T cells and natural killer (NK) cells have been successfully
applied for anticancer immunotherapy. These cells are often generated from the patient, but the quality and quantity are hard to control in vivo. Outsourcing to induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) could offer unlimited sources and enable the expansion of this immunotherapy to a larger number of patients [11]. ESCs are isolated from embryos, while iPSCs are induced from somatic cells in culture by overexpressing Yamanaka factors: Oct3/4, Sox2, Klf4, c-Myc. Incubation of iPSCs and ESCs in the growth medium containing NK cell or T cell-initiating cytokines, for example, stem cell factor (SCF, IL-3, IL-7, IL-15, and FMS-like tyrosine kinase receptor-3 ligand promotes differentiation of immune cells.
Stem cells as potential therapeutic carriers
Tumours are considered chronic wound tissue and their microenvironment, constituted by extracellular matrix (ECM) and secreted paracrine factors, can attract the migration of Mesenchymal stem cells (MSCs) [12]. MSCs are multipotent adult stem cells that are present in multiple tissues, including the umbilical cord, bone marrow, and fat tissue. Several immune-related cytokines are chemoattractants for MSCs to prostate cancer, osteosarcoma, multiple myeloma, and breast cancer cells, for example, CXCL16, SDF-1, CCL-25, TNF-α, IL-1β, and IL-6 [13]. Thus, MSCs can be utilised as potential carriers delivering therapeutic agents in treating cancers.
Featured recombinant TNF-α protein
Sino Biological has developed bioactive recombinant TNF-α cytokines from various species, such as human, mouse, cynomolgus, rat, ferret, and canine. Compared to a competing product, Sino Biological's IL-1β protein demonstrates a higher bioactivity.
MSCs can release nano-sized exosomes, a type of extracellular vesicles (EV), which contain various biological materials, to regulate cell-cell interaction [14]. Anti-tumour mRNA, siRNAs or small molecule drugs were successfully packed into MSCs and target tumor niche to enhance anti-tumor effects or silence tumor-related genes [15]. MSCs can also be utilised to carry anti-cancer drugs via nanoparticles (NPs). MSCs-carried PLA NPs successfully targeted brain tumours and paclitaxel-loaded NPs inhibited lung tumour growth in mice [16].
Cancer cells could also be selectively killed by oncolytic Viruses (OVs), while the naked OVs are easy to be removed by immune cells. Stem cells, like neural stem cells (NSCs), could be promising carriers to protect and deliver OVs to tumour sites [17]. NSCs, originally present in the central nervous system, can self-renew and generate new neurons and glial cells. A previous study found OVs carried by human NSCs in combination with ionizing radiation and temozolomide could enhance cytotoxicity to glioma tumor cells in vitro and increase the survival time of glioblastoma multiforme (GBM)-bearing mice [18].
Both MSCs and NSCs are easier to be engineered to express different genes, which are responsible for the conversion of a prodrug into cytotoxic metabolites towards tumour cells [19]. This gene therapy is called “suicide gene therapy”. There were two clinical trials completed in phase I. One used cytosine deaminase (CD)-expressing NSCs to convert 5-fluorocytosine (5-FC) into tumor-toxic 5-fluorouracil (5-FU) [NCT01172964, completed]. Another one converted ganciclovir from monophosphorylate to triphosphate form, which is more cytotoxic, by Herpes simplex virus thymidine kinase (HSV-TK) expressing MSCs [EudraCT 2012-003741-15, completed]. However, the anti-tumour efficacy relies on dose control, the number of stem cells localised into the tumour microenvironment, and retention in tumour sites.
In this mini-review, we introduced stem-cells-related cancer treatments. Although stem cell therapy has achieved positive results, there are still some side effects to consider, for example, transformation of normal stem cells into cancer stem cells, the chronic GVHD after allogeneic HSC transplantation, the increased immune response, etc. In summary, stem cell technologies have high potentials for tumor treatments but it still needs further efforts to overcome the challenges before they could enter clinical trials.
References
1. Vanneman, M.; Dranoff, G. Combining immunotherapy and targeted therapies in cancer treatment. Nat. Rev. Cancer 2012, 12, 237–251.
2. Wang X, Zhang H, Chen X. Drug resistance and combating drug resistance in cancer. Cancer Drug Resist. 2019;2:141-160.
3. Chu DT, Nguyen TT, Tien NLB, et al. Recent Progress of Stem Cell Therapy in Cancer Treatment: Molecular Mechanisms and Potential Applications. Cells. 2020;9(3):563. Published 2020 Feb 28.
4. Baskar R, Dai J, Wenlong N, Yeo R, Yeoh KW. Biological response of cancer cells to radiation treatment. Front Mol Biosci. 2014;1:24. Published 2014 Nov 17.
5. Hopman RK, DiPersio JF. Advances in stem cell mobilization. Blood Rev. 2014;28(1):31-40.
6. Copelan, E.A. Hematopoietic Stem-Cell Transplantation. N. Engl. J. Med. 2006, 354, 1813–1826.
7. Méndez-Ferrer, S.; Michurina, T.V.; Ferraro, F.; Mazloom, A.R.; MacArthur, B.; Lira, S.A.; Scadden, D.T.; Ma’Ayan, A.; Enikolopov, G.N.; Frenette, P.S. Mesenchymal and hematopoietic stem cells form a unique bone marrow niche. Nature 2010, 466, 829–834.
8. Lee, R.H.; Oh, J.Y.; Choi, H.; Bazhanov, N. Therapeutic factors secreted by mesenchymal stromal cells and tissue repair. J. Cell. Biochem. 2011, 112, 3073–3078.
9. Yu Z, Pestell TG, Lisanti MP, Pestell RG. Cancer stem cells. Int J Biochem Cell Biol. 2012;44(12):2144-2151
10. Codd, A.S.; Kanaseki, T.; Torigo, T.; Tabi, Z. Cancer stem cells as targets for immunotherapy. Immunology 2017, 153, 304–314
11. Iriguchi, S.; Kaneko, S. Toward the development of true “off-the-shelf” synthetic T-cell immunotherapy. Cancer Sci. 2019, 110, 16–22.
12. Aravindhan, S., Ejam, S.S., Lafta, M.H. et al. Mesenchymal stem cells and cancer therapy: insights into targeting the tumour vasculature. Cancer Cell Int. 2021, 21, 158.
13. Jung, Y.; Kim, J.K.; Shiozawa, Y.; Wang, J.; Mishra, A.; Joseph, J.; Berry, J.E.; McGee, S.; Lee, E.; Sun, H.; et al.Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis. Nat. Commun. 2013, 4,1795
14. Fuhrmann, G.; Serio, A.; Mazo, M.M.; Nair, R.; Stevens, M.M. Active loading into extracellular vesicles significantly improves the cellular uptake and photodynamic effect of porphyrins. J. Control. Release 2015, 205, 35–44
15. Kooijmans, S.A.; Schiffelers, R.M.; Zarovni, N.; Vago, R. Modulation of tissue tropism and biological activity of exosomes and other extracellular vesicles: New nanotools for cancer treatment. Pharmacol. Res. 2016, 111, 487–500.
16. Pascucci, L.; Coccè, V.; Bonomi, A.; Ami, D.; Ceccarelli, P.; Ciusani, E.; Viganò, L.; Locatelli, A.; Sisto, F.; Doglia, S.M.; et al. Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: A new approach for drug delivery. J. Control. Release 2014, 192, 262–270.
17. Marelli, G.; Howells, A.; Lemoine, N.R.; Wang, Y. Oncolytic Viral Therapy and the Immune System: A Double-Edged Sword against Cancer. Front. Immunol. 2018, 9, 866.
18. Duebgen, M.; Martinez-Quintanilla, J.; Tamura, K.; Hingtgen, S.; Redjal, N.; Shah, K.; Wakimoto, H. Stem Cells Loaded With Multimechanistic Oncolytic Herpes Simplex Virus Variants for Brain Tumor Therapy. J. Natl. Cancer Inst. 2014, 106
19. Sage, E.; Thakrar, R.M.; Janes, S.M. Genetically modified mesenchymal stromal cells in cancer therapy.Cytotherapy 2016, 18, 1435–1445.
