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Cancer is most challenging to cure because of drug resistance. Cancer stem cells (CSCs) are the reason behind cancer development as a mass-shaped tumor, metastasis, and drug resistance for all the numerous ways in which drug resistance occurs in cancer. Isolation of CSCs and addition of new treatment protocols against CSCs must be added in the improvements for increased treatment of cancer. The following presents advance and challenge towards CSC targeting.
Cancer Stem Cells (CSCs) Information
CSCs are an infrequent population of cancer cells possessing stem-like properties such as self-renewal, differentiation, and tumorigenicity. CSCs are chemoradioresistant, i.e., chemoradio-resistant, and also guilty of tumour relapse and metastasis. Targeting and elimination of CSCs is hence the largest need of present-day oncology science.
CSCs occur in the majority of all forms of cancers including breast cancer, lung cancer, glioblastoma, colorectal cancer, and leukemia. They are refractory to treatment for a multitude of reasons including their quiescence, anti-apoptosis, and crosstalk with the tumor microenvironment.
Advances in Targeting Cancer Stem Cells
Much of the promising work in cancer in recent years has established some promising avenues for therapy of CSCs. The most promising among them are:
1. Targeting CSC Surface Markers
There are certain surface markers that have been found in CSCs where they can be recognized in the case of cancer stem-like cells and are CD44, CD133, ALDH1, and EpCAM. The above mentioned monoclonal antibody or small molecule targeted markers are lethal to CSCs.
- Monoclonal Antibodies: Preclinical models based on anti-CD44 monoclonal antibodies as new molecules for inhibiting tumor growth and self-renewal of CSCs are under development.
- CAR-T Cell Therapy: CAR T-cell therapy whose therapeutic potential for hematologic malignancies is yet to be found is also being explored as CSC-marker-mediated treatment of solid tumors.
2. Targeting CSC Signaling Pathways
CSCs share stemness and survival signaling pathways. Treatments that aim to silence such pathways
- Wnt/β-catenin Pathway: It is one such pathway which is activated when CSC self-renewal is being performed. LGK974 (Wnt inhibitor) is under study to ablating CSC function.
- Notch Pathway: Notch pathway signaling is also targeted by CSCs for proliferation. The pathway is inhibited by gamma-secretase inhibitors (GSIs) as a prophylactic strategy to suppress its activity.
- Hedgehog Pathway: Hedgehog pathway, another regulator of CSC importance, and its inhibitor like Vismodegib are designed to block its function.
3. Epigenetic Therapies
Epigenetic modifications, i.e., histone adjustment and DNA methylation, play a role in CSC survival. Epigenetic silencing of the enzymes causes repolarization of CSCs to responsive phases.
- Histone Deacetylase (HDAC) Inhibitors: Vorinostat and Panobinostat drugs are able to regulate gene expression in a manner that can block CSC survival.
- DNA Methyltransferase (DNMT) Inhibitors: Decitabine and Azacitidine induce CSC activity and enhance chemotherapy.
4. Metabolic Targeting of CSCs
A few of the metabolic features of the CSCs are accountable for their resistance to stressful situations, i.e., hypoxia. Targeting CSC metabolism is a new field:
- Inhibition of Oxidative Phosphorylation (OXPHOS): CSC-mitochondrial respiration.
- Metformin and IACS-010759 classes of drugs block this energy metabolism pathway.
Glutamine Metabolism Inhibition: Glutamine is a fuel used by CSCs and therefore glutaminase inhibitors have traditional therapeutic value.
5. Nanotechnology-Based Therapies
Nanoparticles can be targeted to CSCs, and nanoparticles can be engineered in such a manner that they specifically target CSCs, and drug delivery would not only be improved but drug side effects would reduce. Lipid nanoparticles and polymer nanoparticles are researched for the drug targeting CSC delivery to cancer cells.
Challenges to Successful CSC Therapies
There are a few others that have to be de-mystified in order to actually address CSCs in spite of all that has been attempted so far:
1. Heterogeneity of CSCs
CSCs are gigantically heterogeneous, i.e., can be of a different kind even in the same cancer or even possibly in two people. Heterogeneity is not one-size-fits-all.
2. Plasticity of CSCs
The plasticity of CSCs is that they can change states, and they are hard to target individually.
The Non-CSCs can change states to CSC state-like states and are held responsible for cancer recurrence even when targeted at CSCs.
3. Therapeutic Resistance
Most of the drugs cross the CSCs through multiple mechanisms, i.e., drug efflux pumps like ABC transporters, increased DNA repair, and cross-talk between the CSCs and the tumor microenvironment. All these resistances need to be broken through combination therapy with activity against more than one pathway at the same time.
4. Non-uniform CSC biomarkers
While many CSC surface markers have been found, none of them are CSC-specific. More advanced biomarkers would have to be created if one were to target the CSCs effectively without a system through which normal stem cells could be targeted.
5. Challenges in Drug Delivery
The majority of CSC-targeting treatments are burdened with the issue of drug delivery, especially in solid tumors whose CSCs reside in hypoxic and poorly perfused microenvironments. Efforts must be made to engineer drug delivery platforms like nanoparticles and ADCs in a way that therapeutic efficacy will be optimized.
Future Directions in CSC Research and Therapy
1. Combination Therapies
The best hope to eliminate resistance against CSC is two-dimensional strategy by combined treatment with CSC-targeting treatment and traditional treatment in the form of radiotherapy, chemotherapy, and immunotherapy. Multi-dimensional strategy will then best target CSCs and bulk cancers.
2. Personalized Medicine
The sophisticated proteomic and genomic profiling technologies are making it feasible to treat the CSC on an individualized basis. The researchers can now tailor the drugs in a manner such that they become effective with lesser toxicity for the treatment of an individual patient depending upon his CSC profile.
3. CRISPR-Based Gene Editing
Gene-editing tools like CRISPR-Cas9 are of unprecedented potential for modulation of CSC genetic susceptibility, and it possesses a new hope for their molecule-level annihilation as a cure.
4. CSC Niche Targeting
CSCs are engaging with their tumor microenvironment (TME), wherein survival signals are being transmitted to them. Modulation of CSC niche—i.e., fibroblasts, immune cells, and extracellular matrix elements—can be used to maximize the therapeutic effect.
Conclusion
Cancer stem cells are ultimate refractory targets of cancer biology that are drug-resistant, metastatic, and tumorigenic in nature. Owing to such exquisite therapeutic targets’ identification, e.g., CSC surface molecules, immune evasion machinery, signaling, and metabolism, knowledge was acquired. All above notwithstanding, some of them—drug resistance, plasticity, and heterogeneity—could not be achieved. New technologies in the form of combination therapy, target therapy or personalized medicine, and new drug delivery systems must be discovered based on hope that these limitations may be avoided. With further researches, CSC-targeted therapy will be a revolution in cancer therapy and save the patients.
