Introduction
Stem cells constitute a primary target of biomedical research. Research evidence links these undifferentiated cells to different cancers, including colorectal cancer. The crypts (compartments) in the colorectal tissues contain stem cells at their bases that proliferate into new cells to supplant damaged cells lining the colon (Reza et al. 69). This process is usually controlled; however, a malfunction may lead to an uncontrollable production of malignant cells by the stem cells, causing colorectal cancer.
Despite the genetic basis of colorectal tumours being well known, the existing remedies are less effective in treating late stage cancers. In addition, although current therapies are only able to achieve significant colorectal cancer remission, recurrence is common, especially in late stage cases (Garza-Trevino, Said-Fernandez, and Martinez-Rodriguez 113).
Research shows that the re-emergence of disease after therapy, e.g., radiotherapy, results from stem cells in the affected tissues that are unresponsive to conventional treatments (Reza et al. 72). Thus, it is hypothesised that these stem cells produce new malignant cells, hence, the recurrence. Stem-cell therapy methods destroy these particular cancerous stem cells to treat colorectal tumours and prevent relapse. This study evaluates the current research evidence for stem cell therapy in the treatment of colorectal cancer.
Goals of the Study
This study aims to evaluate stem cell therapies for colorectal cancer. Its objectives include (1) examining standard therapies used against colorectal stem cell cancers, (2) analysing the treatments being developed in vitro and (2) reviewing new techniques that have reached the clinical trial stage.
Important Methods Used
Stem cells play a critical part in the colorectal tumour initiation and growth. Therapeutic approaches against colorectal cancer involve bio-molecules and factors that inhibit signal transduction and receptors like “CD123, CD44, and Lgr5”, among others (Yassin et al. 401). The novel therapeutic methods used against colorectal cancer stem cells ranges from antibodies and antibody constructs to engineered nanoparticles that target cancerous stem cells in the colon.
Interleukin-4 blocking factor has been used to stimulate the uptake of oxaliplatin drug by drug-resistant colorectal stem cells (Yassin et al. 403). Another antibody, anti-EREG, has been used to stop metastatic cancers in the colon. In one study, Anti-EREG was shown to be effective in both xenograft tumours and colorectal models that contain a large number of cancerous stem cells (Kobayashi et al. 638).
Similarly, formulations of antibody constructs have also been used to destroy stem cells that generate malignant tumours in a limited fashion to prevent colorectal cancer relapse. The antibodies target markers, such as CD44 and CDCP1, highly expressed in colorectal cancer stem cells compared to normal stem cells (Kobayashi et al. 638).
Nanotechnology is novel therapy against cancerous stem cells causing colorectal cancer. It entails the use of nano-particles as systems for targeted drug delivery to enhance the efficacy of conventional treatments (Reza et al. 76). The nanocarriers have been shown to be effective in the targeted destruction of cancerous stem cells.
They enhance the penetrability of intravenous infusions or drugs to the nuclei of malignant stem cells. A micelle infusion containing oxaliplatin enclosed in a “chitosan vesicle, i.e., CSO-SA/OXA micelle” has been shown to be efficacious in delivering large amounts of the drug to the cancerous stem cells of the colon both in vitro and in vivo (Liu et al. 279). A high concentration of the cytotoxic agents kills the cancerous stem cells and prevents recurrence.
Besides drug delivery, solid lipid nanoparticles (SLNs) have also been used in the local treatment of colorectal tumours. The SLNs facilitate the controlled emission of the 5-FU drug in cells derived from colonic tumours in vitro (Yassin et al. 401). The cells take up the nanoparticles through endocytosis, which allows the 5-FU molecules to reach the affected cells via diffusion. The same approach is used in the treatment of chemoresistant colorectal stem cells.
Another novel method involves siRNA-mediated silencing of efflux mechanisms expressed in cancerous stem cells (Liu et al. 280). For example, the silencing of MDR1 protein using nanocarriers made of “polyethylene glycol (PEG), polyethyleneimine, and dilinoleyloxy-3-dimethylaminopropane (a cross-linker)” have been shown to be effective in delivering siRNA to chemoresistant colon cancer stem cells (Liu et al. 282).
The siRNA delivered this way achieves a silencing efficiency of over 90 percent. Organic nanoparticles carrying siRNA show enhanced efficiency in MDR1 silencing, which improves the uptake of paclitaxel drug by colon malignant stem cells (Liu et al. 282).
Silver nanoparticles also stimulate apoptotic pathways in colorectal cancer cells expressing p53 (Junghanns and Muller 298). In addition, in vitro assays have shown that these nanoparticles show bactericidal properties, and thus, could prevent recurrent infections in patients (Junghanns and Muller 299).
The n-3 polyunsaturated fatty acids (PUFAs) have also been evaluated for potency against cancerous stem cells. Reza et al. evaluated the strength of n-3 polyunsaturated fatty acids (PUFAs) on the growth of stem cell models (Reza et al. 75). The study found that the PUFAs, particularly docosahexaenoic acid, at a high dosage inhibit cell growth in vitro by up to 71.1% within 72-hour duration (Reza et al. 76). The acids increase the apoptosis of the colorectal cancer stem cells by 12.9% at high concentrations.
Investigators have developed a treatment that could be used with radiotherapy or chemotherapy to treat colorectal cancer. The adjuvant therapy induces the Wnt signalling pathway to promote colorectal repair after chemotherapy (Zhou et al. 112). The pathway plays a role in tumorigenesis that causes cancer. The activation of the Wnt pathway in the colorectal stem cells has been shown to enhance the efficacy of chemo- and radio-therapies by preventing cell damage (Zhou et al. 117).
Wnt signalling pathway is stimulated when “stli2 binds to its receptor Robo1” in the intestinal stem cells (Zhou et al. 112). Further, Wnt agonist (LRP6) can induce cell and tissue repair in the colon via the same pathway. In this way, the damaging effects of chemotherapy and radiotherapy can be reversed to promote patient outcomes and prevent metastatic cancers.
The adjuvant therapy has many advantages over conventional treatments. It has been used to offer protection against colorectal cell damage due to chemotherapy and radiotherapy and prevent metastatic cancers. The stem cells used in this technology are obtained from the colorectal tissue, which avoids the ethical issues associated with the embryonic stem cells. The method has been shown to be active in vitro (cells) and in vivo (mice).
Most Important Findings
The primary treatments against stem cells causing colonic cancer are antibodies and nanoparticles. Preclinical and phase I trials of an antibody called solitomab, which is a recombinant single chain mAb that targets CD133 receptors has been shown to hinder the proliferation of advanced stage solid colonic tumours (Junghanns and Muller 301).
Another antibody, catumaxomab, a recombinant antibody containing IgG2a and IgG2b, has undergone phase I-III trials as a candidate for colorectal cancer treatment (Junghanns and Muller 303). AVE1642, which is a recombinant IgG1 mAb that targets IGR-IR receptors, has also reached phase III clinical trial (Junghanns and Muller 305).
The preclinical trials of two antibodies, figitumumab and OMP-21 M18 (demcizumab), have indicated their effectiveness in localised treatment of cancerous stem cells (Garza-Trevino, Said-Fernandez, and Martinez-Rodriguez 115). The two antibodies target the IGF-IR and DLL4 receptors respectively.
In contrast, OPM-18R5 or vanticumab derived from IgG2 mAb antibody has reached phase I clinical trials (Garza-Trevino, Said-Fernandez, and Martinez-Rodriguez 116). This antibody construct is being used with conventional drugs that target cancerous stem cells in the colon.
Nanoparticles facilitate targeted drug delivery to the malignant stem cells. The nanoparticles undergoing preclinical trials include the MDR1-targeting siRNA and the oxaliplatin-containing micelle (CSO-SA/OXA) (Liu et al. 279). The siMDR1 is a lipid nanocarrier targeting the multidrug resistance protein (MDR1) that causes the efflux of cytotoxic agents from the cancerous stem cells (Liu et al. 282).
The CSO-SA/OXA micelles are specific to cancer stem-like cells that are chemoresistant (Liu et al. 284). In vitro tests of the micelles have been conducted on the human colon cancerous stem cells bearing the CD133 and CD24 biomarkers (Liu et al. 284). On the other hand, adjuvant therapy, which activates pathways essential in cell repair, enhances the efficacy of conventional treatments.
Discussion
The current study was undertaken to examine therapeutic strategies used to treat a subpopulation of cancerous stem cells in the human colon. Clinical research focuses on antibodies and nanoparticles used in combination with conventional drugs to destroy the stem cells causing the malignancy. The methods utilise the biomarkers, such as CD133, present on the cancerous stem cells, but absent in healthy cells, to identify and destroy the malignancy. The recombinant antibodies target specific receptors, such as IGF-IR and DLL4.
On the other hand, the nanoparticle-drug complex, such as the CSO-SA/OXA micelle increases the efficacy of conventional drugs by increasing the concentration of cytotoxic agents in the stem cells (Liu et al. 279). Chemoresistant cells pump out drugs through the multidrug efflux pumps. Thus, the micelle helps overcome the resistance by increasing drug concentrations in the affected cells. Most of these treatments have reached phase III clinical trials, presenting effective multimodal therapies for colorectal cancer.
Conclusion
Colorectal cancer reduces patient outcomes because of its high recurrence rate after chemotherapy. Uncontrolled division of crypt progenitors in the colon produces the colorectal tumours. Conventional treatments do not completely eradicate the specific stem cells causing the malignancy.
Current research focuses on antibodies and nanoparticles combined with drugs that target and destroy the affected cells. Antibodies and antibody constructs, such as solitomab, and lipid nanoparticles (micelles) have undergone clinical trials as candidate therapies for colorectal cancer stem cells. These treatment strategies utilise biomarkers to distinguish cancerous stem cells from healthy ones.
Works Cited
Garza-Trevino, Elsa, Salvador Said-Fernandez, and Herminia, Martinez-Rodriguez. “Understanding the Colon Cancer Stem Cells and Perspectives on Treatment.” Cancer Cell International 15.1 (2015): 112-117. Print.
Junghanns, John, and Randy Muller. “Nanocrystal Technology, Drug Delivery and Clinical Applications.” International Journal of Nanomedicine 3.3 (2008): 295–309. Print.
Kobayashi, Shinta, Hisafumi Yamada-Okabe, Masami Suzuki, Osamu Natori, Atsuhiko Kato, and Koichi Matsubara. “LGR5-positive Colon Cancer Stem Cells Interconvert with Drug-Resistant LGR5-Negative Cells and are Capable of Tumor Reconstitution.” Stem Cells 30.12 (2012): 631–644. Print.
Liu, Chi, Zhao Guan, Jin Liu, Ma Ning, Chivukula Pang, and Perelman Leight. “Novel Biodegradable Lipid Nano Complex for Sirna Delivery Significantly Improving the Chemosensitivity of Human Colon Cancer Stem Cells to Paclitaxel.” Journal of Control Release 140.3 (2009): 277–283. Print.
Reza, Mohammad, Parinaz Ahangar, Vahid Nejati, and Reza Habibian. “Treatment Of LS174T Colorectal Cancer Stem-Like Cells With N-3 Pufas Induces Growth Suppression Through Inhibition Of Surviving Expression And Induction Of Caspase-3 Activation.” Cellular Oncology 39.1 (2016): 69-77. Print.
Yassin, Alhamy, Mike Anwer, Hatmi Mowafy, Mohammed El-Bagory, Amin Bayomi, and Ibrahim Alsarra. “Optimisation of 5-Flurouracil Solid-Lipid Nanoparticles: A Preliminary Study to Treat Colon Cancer.” International Journal of Medical Science 7.6 (2010): 398–408. Print.
Zhou, Wei-Jie, Zhen Geng, Jason Spence, and Jian-Guo Geng. “Induction of Intestinal Stem Cells By R-Spondin 1 and Slit 2 Augments Chemoradioprotection.” Nature 501.1 (2013): 107-121. Print.