Stem Cell Technology in Regenerative Medicines and Cancer Treatment: Towards Revolution in Clinical Success

Review Article

Austin J Cancer Clin Res. 2021; 8(2): 1094.

Stem Cell Technology in Regenerative Medicines and Cancer Treatment: Towards Revolution in Clinical Success

Muhammad Mukheed1*, Alisha Khan1, Husnain Karim Riaz3, Irfan S3, Kainat Amjad2, Hina Ilyas1, Aimen Afzal1, Shehreen Sohail3, Fareeha Sohail3, Zoha3, Raza MA2, Hayat U2, Khalid MU1, Amna Nahid4, and Farooq W3

1Department of Biotechnology University of Gujrat, Gujrat, Pakistan

2Department of Biological Science University of Sialkot, Sialkot, Pakistan

3Department of Microbiology, University of Central Punjab, Lahore, Pakistan

4Department of Microbiology, Government College University Lahore, Lahore, Pakistan

*Corresponding author: Muhammad Mukheed, Department of Biotechnology, University of Gujrat, Gujrat, Pakistan

Received: July 15, 2021; Accepted: August 03, 2021; Published: August 10, 2021


Stem cells are undifferentiated, immature, and unspecialized cells having huge potential for differentiation and proliferation into the specialized functionalized cells. More recently, CSC has been described in breast cancer and brain tumors where they make up as few as 1% of the cells in a tumor. The features of cancer stem cells are just like normal stem cells but their replication rate many times faster than normal cells. Regenerative medicines are based on stem cells, are potentially useful to regenerate damaged cells, tissues, organs and replace cancer cells with normal cells. Induced pluripotent stem cells are the most important candidates for regenerative medicines, tissue engineering, cell reprogramming, and 3D printing. Cancer Stem Cells (CSCs) have a tumorinitiating capacity and play crucial roles in tumor metastasis, relapse and chemo/ radioresistance. Because CSCs are resistant to chemotherapeutic drugs and cause recurrence of cancer and also have the ability to be regenerated; they can cause serious problems in the treatment of various cancers. Numerous biocompatible biomaterials, miRNAs, nanomaterial, artificial intelligence, and machine learning are uses to reprograms stem cells into regenerative medicines for the treatment of cancer. The present paper describes the applications and importance of stem cells in regenerative medicines, cancer stem cells targeting therapies, and the role of miRNAs in cancer stem cells targeting.

Keywords: Cancer stem cells; Induced pluripotent stem cells; Regenerative medicines; Tissue engineering; Biomaterial; miRNAs; Artificial intelligence


The stem cells are immature and unspecialized cells that have robust self-renewable potential and the ability to differentiate into all mature and specialized cells. These cells can replace the damaged and defective cells and play important role in the regeneration of damaged body parts. The role of stem cells in regenerative medicines and therapies has been widely anticipated [1,2]. The adult bone marrow stem cells can replicate repeatedly and differentiate into specialized mesenchymal tissues such as bones, cartilages, muscles, tendons, and others. The self-renewable ability and potential to differentiate into all cells evaluate the importance of stem cells in regenerative medicines and tissue engineering. Stem cells are isolated from the patient body and expand by ex vivo culturing and by combining with biodegradable and biocompatible inserted into the patient body where they grow normally to repair damaged or injured cells and tissues [3]. Human adipose tissue-derived stem cells have ideal applications in tissue engineering and cancer treatment. Adipose-derived stem cells are more beneficial and reliable than mesenchymal stem cells because these cells are easily isolated and have huge potential to differentiate into osteocytes, hepatocytes, adipocytes, cardiomyocytes, pancreatic beta cells, neural and endothelial cells. Low immunogenicity, secretion of trophic factors, and immunosuppressive properties of ADSCs make them more relevant and preferable in regenerative medicines and cancer treatment [4]. The human-induced pluripotent stem cells assemble with embryonic stem cells in reprogramming and self-renewable characteristics and use cardiac research from the last ten years. hiPSC derived cardiac myocytes are a potential platform for the human disease model and an important tool for drug delivery and testing. In advance, hiPSCs are a common source of stem cells in human-animal regenerative models because these cells capitulate phenotypic differences due to genetic variations [5]. The glioblastoma contains a rich amount of tumor-causing cancer stem cells. These cells make a contribution to tumor propagation and therapeutic resistance but the mechanism is not known until. According to recently performed studies the CD36 expression was noted in GBM which are rich in cancer stem cells and when these CD36 are expressed with CD133 and integrin alpha 6 their selfrenewable and tumor initiation capacity declined. Moreover, it has been confirmed that the ligands of CD36 are oxidized phospholipids present n GBM and the proliferation of CD36 decreases when exposed to oxidized low-density lipoproteins. Hence the enhanced expression of scavenger receptors provides survival and metabolic advantages [6]. Scientists have strong shreds of evidence that cancer cases are increases due to the transformation of normal cells into cancer cells. Sometimes after conventional therapies cancer cells again proliferate and tumors formed. This chemoresistance affects cancer stem cells arise due to the activation of B cell-specific Moloney murine leukemia virus integration site 1 (BMI1). BMI1 has an important role in the cell cycle, regulation, and proliferation of normal and cancer stem cells. It is also suggested that BMI1 are present on cancer stem cells and after therapy, these factors are reactivated and form tumor again [7]. Several pluripotent transcriptional factors such as SOX2, Nanog, KLF4, OCT4, and MYC are potential biological activators of cancer stem cells. It is also confirmed that several intracellular signaling pathways including Notch, JAK-STAT, Wnt, TGF, PPAR, and P13K/AKT/mTOR and extracellular factors hypoxia, vascular niche, cancer-associated fibroblast, cancer-associated MSCs, and exosomes are proliferator and regulator of cancer stem cells [8]. Due to these abnormalities, regenerative medicines are preferred to treat cancer because regenerative medicines are based on stem cells and replace the tumor-causing cells with normal cells.

Personalized Regenerative Medicines

Personalized medicine is referred to as patient-specific therapeutic agents. Regenerative medicines and cell therapy are depending on cells-based products to personalized medicine. Mesenchymal stem cells, embryonic stem cells, and induced pluripotent stem cells are useful in targeted therapies. Due to fewer immune rejection chances, induced pluripotent stem cells have been introduced as a therapeutic candidate for personalized regenerative medicines. It also noted that multiple factors such as recipient factors, donor factors, and overall body environment for stem cell activation are important to achieve personalized stem cell therapy. A lot of technologies such as molecular diagnostic tools play important role in the development of regenerative medicines. Embryonic stem cells have enormous potential in regenerative medicine but because of highly immune rejection chances and ethical issues these are prohibited and somatic cells are reprogrammed in culture media and pluripotency induced [9]. In culture media, somatic cells are undergo reprogramming by reprogramming factors such as Nanog, Oct4, Sox2, and Lin28 [10]. Due to self-renewable and potential to differentiate into all cell kinds, stem cell provides a significant platform for regenerative medicines. Human induces pluripotent stem cells are used in the treatment of cancer, cardiovascular, renal, kidney, neurological disorders, Parkinson’s disease, and spinal cord injury act. It has been illustrated that human adipose-derived stem cells are a kind of progenitor stem cells and a major source of pluripotent stem cells. ADSCs are also substituted for bone marrow MSCs as a secondary source of regenerative medicine [11]. The mesenchymal stem cells are adult tissues that undergo multilineage differentiation when cultivated and expand in-vitro. Groups of researchers have been derived MSC from iPSCs (iPSCs-MSC) as an alternative source of MSCs personalized regenerative medicine and also applied in direct cell therapy, gene therapy ad tissue engineering [12]. The experimental studies are conducted to generate cardiomyocytes from iPSCs by inducing embryonic body formation and treatment with bone morphogenic protein 4, Activin A, and inhibition of Wnt signaling. These derived CMs are heterogeneous, need maturation and purification for in vitro CMs mimicry. Mature CMs are used in regenerative medicines by developing tissue-engineered cardiac patches [13]. The human body loses tissues and organs in trauma, disease, and defects. As the human body has a very low potential to regenerate damaged organs and tissues as compared to amphibians and due to the shortage of organs for transplantation scientists need to develop reliable source organs and tissues. Tissue engineering and regenerative medicines are employing biological and engineering to create new organs and tissues via three-dimensional bioprinting. Stem cells and scaffold of specific organ in a specific culture media will develop into required organ or tissue. 3D bioprinting is the most advanced tool in personalized regenerative medicines and tissue engineering [14]. Biological wastes such as urine are also inhabitants of cells that have the self-renewable ability and differentiation potential which originally derived from nephrons, renal pelvis, bladder, and ureters. The urine-derived stem cells are phenotypically mimicking with bone marrow mesenchymal stem cells and reprogrammed into an induced pluripotent stem cell. These urine-derived iPSCs have potential use in personalized regenerative medicines, tissue engineering, and drug delivery. For example, bone marrow MSCs are not differentiated efficiently into the urothelial cell so UDSC-iPSCs have better performance and huge potential for urothelial cell production. Urine-derived stem cells are also used in bone regeneration, neural cell regeneration, and the treatment of prostate cancer [15]. The genome editing tools such as zinc finger nucleotide, TALEN, and CRISPR Cas9 system has important application in tissue engineering and personalized medicines. When tissues, organs, or cell lines are proliferating in vitro, cell proliferation and reprogramming are enhanced by altering the expression rate of specific genes. According to recently performed studies, it is confirmed that CRISPR, CRISPRi, and CRISPRa are mostly used to edit gene or regulating gene expression for bone regeneration, neural cell regeneration, and treatment of prostate cancer, leukemia, skin cancer, and other diseases [16]. As we describe above iPSCs are specific kinds of stem cells and have huge potential in personalized medicine because these cells are ethically accepted and following reprogramming injected back into damaged tissue or organ by vectors such as retrovirus and lentivirus. Sometimes reactivation of viral transgene due to incomplete silencing and interfering with induced iPSCs proliferating potential cause tumorigenesis. So, retrovirus and lentivirus use in the clinical field is prohibited. Hence non-viral tools for injection of Yamanaka factors (Sox2, Oct4, c-Myc, and Klf4) are developed such as RNA or DNAbased electroporation and polymer or lipid-based nanoparticles. As small-sized, high surface area and lipid-based nanoparticles are not interacting with the host cell genome, they are employed to deliver reprogramming factors on specific sites [17]. Recently a technology named direct cell reprogramming or transdifferentiation was developed in which one somatic cell is directly programmed into another cell without induction of pluripotent state. Direct cell reprogramming can differentiate abundant cells in the body into desired tissues or cells therefore this technology has an advanced role in regenerative medicines. Several cells such as neuronal cells, skeletal myocytes, and more which have the potency to regenerate damaged tissue or cells, replace cancerous cells are generated through direct cell reprogramming [18].

Cancer Stem Cell-Targeted Therapies

Cancer stem cells are a subpopulation of cells that have similar differentiation, self-renewable, and proliferation activities as normal somatic and embryonic stem cells. Multiple surfaces and enzymatic markers are characterized for the identification of cancer stem cells such as CD34+, CD38- and cancer stem cells express multi-drug resistance proteins and upregulated gene expression. There multiple classes of cancer stem cells such as breast cancer stem cells, brain cancer stem cells, leukemia stem cells [9]. There are several cancer celltargeted therapies. One of the most important signaling pathways is the Notch pathway which is revealed as the target for different kinds of tumors. The activation of notch occurs when ligand bind with notch receptor which followed cleavage via ADAM protease and gammasecretase and results in exposure of notch intracellular domain. This NICD transport to the nucleus where it binds with cancer stem cells transcription factors and becomes converted into an activator of the Notch gene. The use of gamma-secretase inhibitors and antibodies is successful to treat breast, pancreatic, and renal cell carcinoma [19]. It has been noted that the complicated phenotypes and biological behavior make it difficult to purify cancer stem cells and further culturing because cells may lose their stemness. Nowadays multiple receptor/markers, cancer stem cells related factors are recognized to purify and therapeutically target CSCs. Some important cancer stem cells related markers are ABCG2, ALDH1, CD133, CD9f, OCT4, OPN, and SOX2. These stem cell markers provide an accurate and easy approach to identify cancer stem cells [20]. Recently performed studies proposed a dual-targeting strategy to target cancer stem cells. In this strategy, the agent VS 5584 is used as a dual inhibitor of mTORC ½ and class IPI 3-kinase which results in inhibition of tumor development and CSCs loss their ability to form tumors [21]. The cancer stem cells are developed resistance against conventional therapies because CSCs are localized in a microenvironment named “vascular niche”. This niche has a major role in resistance against conventional therapies. This problem force scientists to move towards intrinsic and extrinsic factors-based targeting. These therapies are based on DNA repairing systems, Scavengers, and multiple drug transporters [22,23]. In a recently performed study it is proved that the milk protein alpha casein when overexpressed in Triple-Negative breast cancer lines, the tumor developing activity of cancer stem lines declines because the alpha casein protein inhibits the expression of STAT3 and HIF-1alpha. Moreover, the alpha casein protein also reduces the expression of cancer-associated fibroblasts [24]. Cyclopamine a sterile like compound is bind and inhibits SMO protein by competing for binding with Vitamin D which in turn depress the tumor formation ability of cancer stem cells. It is also investigated that cyclopamine compounds reduce the cancer cell proliferation in prostate and gastric cancer cell lines [25]. Targeting cancer cell surface proteins with antibodies, ABC transporter inhibition, and ALDH enzymes along with small molecules are useful in tumor reduction. As we know that lung cancer cells multiple markers, one is CD133. CD133 marker in association with OCT4 gene. The high expression of OCT4 induces self-renewable ability in CD133 marker cells. The siRNA inserts to knock down OCT4gene expression which results in loss of the self-renewable ability of CD133 cells and tumor formation activity suppressed. Alternatively, it is suggested that α6β1 integrin is involved in the genesis of cancer stem cells and helps in cancer cells’ survival of CSCs. By targeting integrins the cancer stem proliferation can be prohibited [26]. The GSK3β is involved in cancer pathways especially it is upregulated in breast cancer. The high expression of GCK3β has a pivotal role in the survival of Triple Negative Cancer. Inhibition of this pathway decreases the cancer cell markers proliferation and stemness of cancer stem cells. The Wnt- β-catenin pathway inhibits via GSK3β which play important role in tumor suppression [27]. Overexpression of proliferative pathways in cancer cells is in association with tyrosine kinase activity of membrane receptors and cytoplasmic proteins. Tumor cells with overexpression of EGFR receptors are targeted by the application of EGFR tyrosine kinase inhibitors. In the same way in breast cancer, HER2 receptors are overexpressed and the employment of HER2 inhibitors reduces proliferation and differentiation of these markers. HER2 receptors have an important role in the maintenance of stemness in cancer stem cells [28].

As we described earlier, the proliferation and self-renewable activity of cancer stem cells are responsible for resistance against chemo and radiotherapies. The cancer stem cells also have a huge capacity for DNA repairing which also contributes to resistance. In glioma CD133+ greater expression of DNA repair checkpoints is present. The damaging or inhibition of these checkpoints leads to a reduction in tumor formation. Target eliminations of cancer stem cells take part in the inhibition of tumor generation. CSCs have many surface markers, providing a platform to develop strategies that directly target these markers [29]. Recently a group of scientists proved that Chimeric antigen T cells receptors have an immunotherapeutic approach to target cancer cells. The chimeric T cells are command to express artificial receptors which have a targeting domain from antibodies connected with an intracellular domain. The antibodies responsible for targeting surface antigens on CSCs are the origin of chimeric antigen receptors [30]. Natural killer cells have revolutionized the ability in lyses of cancer stem cells. By increasing the expression of natural killer cells ligands as NKp30 and NKP44 scientists improve the cytotoxic activity of NK against CSCs [31]. According to recently conducted studies, melatonin decreases colony formation, invasion, proliferation, and migration of melanoma cells and promotes cell arresting, stemness decreasing in cancer stem cells by stimulating vemurafenib. By repudiating the nucleus translocation of NF-kBP50/p65 and bind it with promoters named iNOS and hTERT, melatonin intensifies the anti-tumor effect of vemurafenib [32]. Epigenetic alterations have a significant and synergistic role in gene expression and useful in carcinogenicity. Important and specific pathways as DNA methylation, regulatory RNAs, and chromatin remodeling are organized in cancer cells especially via epigenetic mechanisms. Through epigenetic mechanisms, phenolic compounds for example polyphenols having anticarcinogenic, anti-tumor, antiinflammatory, and anti-oxidant activities, neutralize and suppress cancer stem cells proliferation, development, microenvironment, and their metabolisms. Hence use of these phenolic compounds is helpful in the treatment of different types of cancers [33]. According to research published in 2019, the NRG fusion proteins are drivers for several cancers as pancreatic, lungs, prostate, and breast cancers. The NRG1 fusion protein binds with HER3 and causes heterodimerization of HER2/3 which leads to increasing downstream signaling pathways and tumor growth. HER2 and HER3 directed antibody called MCLA- 128 is applied directly on cancer stem cell lines. MCLA-128 blocks the binding of ligand to HER3 and decreases downstream signaling and tumor growth shrink [34]. Moreover, a synthetic guanosine analog and antiviral molecule Ribavirin used against hepatitis C also have an anti-tumor capacity. The transcription factors eLF4E are inhibited by ribavirin in leukemia and lymphoma. These factors have an important and crucial role in RNA export and expression of oncogenes such as MYC, BCL2, and BCL6. Ribavirin directly targets two complexes eLF4E and IMPDH. In addition, ribavirin also indirectly targets carcinogenic pathways including EZH2 and MAPK pathway and reduces the tumor burden on cancer cell lines [35]. A nonsteroid and antiandrogen agent enzalutamide is demonstrated as a targeting agent in prostate cancer and androgen receptors activity in castrate resistance prostate cancer. As we know that JAK2 and STAT5 mRNA levels are in peaks in prostate cancer. This evaluated level of oncogene mRNAs is inhibiting by enzalutamide [36]. Recently a new antitumor agent tipifarnib is recognized as the target agent of tumors with HRAS mutation. HRAS is confessing as an oncogene and overexpressed in squamous cell carcinoma. The activity of HRAS is synchronized by the enzyme farnesyltransferase. Tipifarnib inhibits this enzyme and results in decreasing HRAS expression and tumor growth diminished but until tipifarnib in trial phases [37-39]. Many therapies are in trial phases, some are in use but these therapies are not completely treating cancer. Now the revolutionized steps are taking to target cancer stem cells. From last decades it hypothesized that regenerative medicines are accomplished in cancer stem cells targeting. Induced pluripotent stem cells with genome editing have a mountain approach for cancer stem cells targeting. The cancer stem cells targeting therapies, their mechanism and targeting agents are listed in Table 1.

Citation: Mukheed M, Khan A, Riaz HK, Irfan S, Amjad K, Ilyas H, et al. Stem Cell Technology in Regenerative Medicines and Cancer Treatment: Towards Revolution in Clinical Success. Austin J Cancer Clin Res. 2021; 8(2): 1094.