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Adipocytes are one of the main components of the breast and have been shown to play a role in tumor development. In line with this observation, a few chemopreventive agents have been tested for their efficacy against BC cells. Sulforaphane, which is a compound present in broccoli, has been extensively studied and shown promising results.152 However, the limited understanding about the role of adipocytes in promoting tumorigenesis is limiting the scope of available options to target these adipocytes. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a well-known death receptor that can mediate ligand (TRAIL-R1, TRAIL-R2)-induced apoptosis, in tumor cells. TRAIL-mediated therapies are in Phase I clinical trials for TNBC.153 It has been reported that TRAIL can be a valuable tool for targeting patients who have limited treatment options.153 However, there are some tumors that show resistance to TRAIL therapy, with CSC being major contributors in therapy resistance. The overexpression of anti-apoptosis proteins like c-FLIP can lead to the resistance of anti-TRAIL therapy. Thus combining the c-FLIP inhibition with anti-TRAIL antibodies can lead to an effective eradiation of CSC and thus overcoming therapy resistance.154
Also, the macrophages and monocytes express a large amount of TRAIL receptors, that is, TRAIL-1R and TRAIL-2R. Thus, recombinant TRAIL therapy can help in selectively inducing apoptosis of the tumor-associated macrophages (TAM), which form a primary signaling arm for tumor microenvironment. Therefore, TRAIL therapy can provide dual benefits all together, where it can selectively eliminate tumor cells and also control the pro-tumor signals coming from TAM present in the microenvironment (Figure 4).155
Targeting CSC metabolism
CSCs show a distinct dependency on glucose and mitochondrial metabolism. It is shown that the multipotent cells rely majorly on glycolysis. The stem cell pool of basal-like BC, which is CD44+/EPCAM+, is dependent on aerobic glycolysis. Overexpression of FBP1, which promotes gluconeogenesis and inhibits glycolysis, reduces the number of spheroids in basal-like BC.156 A well-known regulator for mitochondrial metabolism is BCL-2 protein, which forms a complex with Bcl-2-associated death promoter and glucokinase. Inhibition of BCL-2 activation can lead to the inhibition of oxidative phosphorylation (OXPHOS) leading to the reduction of CSC depending on OXPHOS.157Increase in mitochondrial activity can promote metastasis and confer resistance to DNA damage in BC.158 A transcription factor peroxisome proliferator-activated receptor gamma, co-activator 1 alpha (PPARGC1A, also known as PGC-1α), is an important target for cancer cell metabolism as it couples with OXPHOS and supports migration and invasion of cells. This factor has been reported to be highly expressed in BCSCs and its inhibition lead to decreased stemness.159 Fatty acid oxidation is another major arm of supporting tumor cell growth and proliferation. It has been reported that various stem cell pools rely on fatty acid oxidation.160 NANOG is known to repress OXPHOS and activate fatty acid oxidation. Thus using etomoxir, a carnitine palmitoyltransferase-1 inhibitor, could reduce the spheroid formation ability of BC in vitro and also reduced in vivo tumorigenic potential.161 A mitochondria inhibitor VLX600 has been reported to target the quiescent cell pool within the tumor, in vivo.162Salinomycin, which is an antibiotic extracted from Streptomyces albus has been shown to reduce the stemness by targeting the Wnt pathway, which is crucial for maintaining stem cell proliferation.163Wnt signaling is a known regulator of cell metabolism, where a study has shown that using a therapeutic approach of administering Wnt antagonist frizzled-related protein 4 caused metabolic reprogramming, which led to apoptosis of CSC under variable glucose conditions.164 Recent reports suggest that targeting iron metabolism can be fruitful in targeting CSC since altered iron metabolism can cause increase in ROS and oxidative stress.165
Nano-therapeutics against CSC
Nanoparticle (NP)-mediated therapy is an effective strategy of drug delivery for cancer therapeutics. NPs are also being employed for targeting stem cell subpopulations within tumor bulk, where CSC marker-targeted NPs offer an advantage of specificity and precision. Thus using biocompatible polymers like liposome, PLGA, and so on, which are coated with antibodies/aptamers against BCSC-specific markers, can help in specific delivery of chemotherapeutic drug, RNAi, or antibodies to the stem cell population. BCSCs generally show enhanced expression of CD44, and studies have shown that paclitaxel- and salinomycin-loaded liposomal NP coated with CD44 antibody can target the CD44+ CSC population of MDA-MB-231 cells.166 Iron oxide magnetic NPs coated with CD44 antibody and loaded with gemcitabine have been used for targeting the stem cell population in BC.167 These particles have been shown to have an added advantage of hyperthermia. NPs containing a combination of chemotherapeutic agents along with autophagy inhibitor chloroquine (CQ) are an upcoming line of therapy which can target the tumor bulk as well as CSC pool within a tumor.168Doxorubicin and CQ NP have shown to reduce the ALDH high population of MDA-MB-231 cells.
Administration of decitabine, a DNA hypermethylation inhibitor encapsulated in NP made with polyethylene glycol, could sensitize the tumor bulk and CSC population to chemotherapy. Also, when these NPs were combined with doxorubicin, they could reduce the ALDH+ population in mammospheres of MDA-MB-231 cells.169 Anticancer drugs are frequently being incorporated into liposomes, for efficient drug delivery. An anticancer compound ESC8 was used along with dexamethasone (Dex)-associated liposome (DX), to form ESC8-entrapped liposome named DXE, showed promising results in reducing the drug-resistant cell population.170 Drug targets against Notch, TGF-β, and Wnt/β-catenin pathways are also being used in combination with NPs.
NPs are also used to deliver siRNA to tumor. A cationic lipid-based polymer was developed along with an siRNA and TGF-βR-I receptor inhibitor LY364947.171 Similarly, a cationic liposomal delivery of miR-34a could reduce the expression of CSC markers ALDH and CD44, thereby delaying tumor growth.172An interesting observation made by a group showed that graphene oxide (carbon nanomaterial) itself has the potential to induce differentiation of stem cells and reducing their in vitro sphere forming ability, thereby it can be a good source to target tumor bulk as well as the CSC population.173 Carbon nanotubes are capable of mediating a thermal effect, and they have been studied in BC cells where the BCSCs were found to be sensitive to these carbon nanotube thermal therapy.174 Further, conjugation of these carbon-based nanomaterials with stem cell receptor targeting can help achieve specificity. Also, novel methods of gene delivery using NPs are being effectively used to reduce tumor burden. An interesting study showed that specific gene delivery targeting the glucocorticoid receptor using a cationic liposome has the potential to reduce tumor growth in vivo.175
CONCLUSION
BC is a complex and heterogeneous disease, a culmination of a variety of cells that exert influence on one another, thereby making the disease management complex. Cellular/clonal heterogeneity within tumors and disease relapse are the major threats from the clinical point of view. We have now started to understand the quiescent, self-renewable pool of cells within a tumor population, the so-called BCSCs, which can govern the therapy resistance, metastasis, and disease relapse. Also the stem cells have unique mechanisms to withstand drug/radiation insults, for example, presence of large number of drug efflux pumps, and enhanced DNA repair machinery and thus posing big in terms of future developments of cancer therapeutics.
Tumor microenvironment is another key domain helping in maintenance of CSCs. Various elements like cytokine flux, tumor-associated immune cells, stromal cells, and CAFs impact chemokine receptor signaling, cytoskeletal rearrangements, hypoxia, angiogenesis, as well as cell metabolism. Altered cancer cell metabolism is a consequence of cancer condition where the BCSCs depend particularly on glycolysis. Mitochondrial OXPHOS is an alternative backup for stem cell survival. A large number of preclinical and clinical studies are being conducted on today’s date, targeting eradication of stem cell pool at the tumor site. Studies have also begun to explain the concept of CSC plasticity, where the non-CSCs can revert back to CSCs, and therefore, greater attention is needed as it will be indispensable for CSC management. The advancement in nanotherapeutics and nanomedicine is also greatly changing the face of treatment options by providing novel approaches of combining multimode treatment options. Together, all these dimensions added to BC research is surely going to give us an edge in reducing the impact of therapy resistance and improve disease outcomes in future days.
Disclosure
The authors report no conflicts of interest in this work.
Pranay Dey,1,2 Maitreyi Rathod,1,2 Abhijit De1,2
1Molecular Functional Imaging Lab, Advanced Centre for Treatment,
Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai,
India; 2Molecular Functional Imaging Lab, Homi Bhabha National
Institute, Mumbai, India
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Source: Breast Cancer: Targets and Therapy.
Originally published March 7, 2019.
