Stem Cells and Prostate Cancer

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The therapeutic agent should be able to kill the targeted CSC when the antibody—drug complex is either bound to the cell surface or internalized in sufficient numbers 3. Receptor-mediated endocytosis 4 of the payload e. If the targeted antigen on all of the CSCs is sufficiently expressed, the therapeutic agent may eradicate the relapse-causing cells and eventually stop the disease. If for example beta-particles emitted from 90 Y or Lu maximum energy, maximum range, and average linear energy transfer LET equal to 2.

However, if alpha particles emitted from for example At or Bi maximum energy, maximum range, and average LET equal to 7. This means that the likelihood of eradicating the CSCs using alpha-particles greatly exceeds that of using beta particles, especially if the targeted antigen is expressed in low numbers on the CSCs. It should also be noted that, although the range of the alpha particles is in the order of typically only two to three cell diameters, some crossfire will still occur of neighboring eventually untargeted cells. Cell surface targeting of the CSCs may occur via monospecific antibodies against various epitopes expressed by CSCs, e.

It may also be used to deliver nanoparticles NPs at a high concentration and release them within the tumor cell following uptake by CSCs, e. Likewise, liposome NPs may be utilized together with alpha-particle emitters to simultaneously deliver chemotherapeutic drugs, most probably enhancing the therapeutic efficacy.

Cancer stem cells eliminated in prostate cancer | Greater Zurich Area

Epigenetic changes may further induce differentiation and reduce SC characteristics in treated cells, including radioresistance unpublished data. Epigenetic modifications may turn on or off critical genes, and we have previously shown that the epigenetic regulator REST is downregulated in CRPC and associated with dedifferentiation and poor prognosis This article claims that choosing TAT against CSCs might be a way forward to increase the probability of prolonged survival, or even cure, for patients having a metastatic cancerous disease.

Castration-resistant PCa is today an incurable disease, with only a relatively short mean survival after progression, despite development of new drugs during recent years targeting the bulk of the prostate tumor cells. Targeting the root cause of tumor recurrence with efficient RIT methods would most likely result in prolonged survival compared to the conventional treatment concepts of today.

We think that novel alpha particle-based RIT therapies targeting various prostate CSC markers could transform the treatment of resistant metastatic PCa in the near future. Both authors have made substantial, direct, and intellectual contribution to the work and approved it for publication.

Asymmetric Cell Division of A Low-PSA Prostate Cancer Stem Cell

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Castration-resistant prostate cancer: from new pathophysiology to new treatment. Eur Urol 65 2 — New drugs in prostate cancer. Prostate Int 4 2 — Alpha emitter radium and survival in metastatic prostate cancer.

N Engl J Med 3 — Using circulating tumor cells to inform on prostate cancer biology and clinical utility. Crit Rev Clin Lab Sci 52 4 — The molecular and cellular origin of human prostate cancer. Biochim Biophys Acta 6 Pt A — Cancer stem cells, cancer-initiating cells and methods for their detection.

Stem Cells and Prostate Cancer

Drug Discov Today 21 5 — Mechanisms of chemoresistance in cancer stem cells. Clin Transl Med 2 1 Ceder JA. Targeting the mechanisms of progression in castration-resistant prostate cancer. Eur Urol 67 3 —1. Abbas A, Gupta S. The role of histone deacetylases in prostate cancer. Epigenetics 3 6 —9. Bouwman BA, de Laat W. Architectural hallmarks of the pluripotent genome.

N-cadherin promotes epithelial-mesenchymal transition and cancer stem cell-like traits via ErbB signaling in prostate cancer cells. Int J Oncol 48 2 — Radioimmunotherapy for prostate cancer — current status and future possibilities. Semin Nucl Med 46 2 — Bismuth and actinium — generator performance and evolving therapeutic applications of two generator-derived alpha-emitting radioisotopes. Curr Radiopharm 5 3 —7. J Nucl Med 51 2 — Clinical experience with alpha-particle emitting At: treatment of recurrent brain tumor patients with At-labeled chimeric antitenascin monoclonal antibody 81C6.

J Nucl Med 49 1 —8. J Nucl Med 50 7 — Alpha-radioimmunotherapy of intraperitoneally growing OVCAR-3 tumors of variable dimensions: outcome related to measured tumor size and mean absorbed dose. J Nucl Med 47 8 — PubMed Abstract Google Scholar. Cancer Biother Radiopharm 28 2 — Cancer Biother Radiopharm 24 6 — Pharmacokinetics and imaging of Pb-TCMC-trastuzumab after intraperitoneal administration in ovarian cancer patients. The chimeric antigen receptor T cell CAR-T therapy has gained great attention due to the advantages of CAR-T cells in the treatment of malignant tumors of the blood system and has achieved great breakthroughs.

Up to now, there are only two ongoing clinical trials for prostate cancer CAR-T therapy. In this review, we make a systematic summary of the present situation of CAR-T cells in the treatment of prostate cancer and discuss the promise of the application of this technology to prostate cancer therapy. The CARs are fusion proteins constructed by modern molecular biotechnology. CARs are generally composed of three parts: extracellular antigen identification zone, transmembrane zone, and intracellular signal transduction zone.

ITAM plays a crucial role in the transduction of signal to active T cells. T cell-mediated immune response is cellular immunity.

According to the source of antigen, the pathway of activating T cells is different. The antigen presenting cell APC takes in the exogenous antigens and disassembles them into peptides by lysosomal degradation. The complete activation of T cells requires the help of dual signal systems and cytokines. The double signals activate different signaling pathways and a variety of transcription factors to promote the production of cytokines such as IL-2 that can active T cells fully and make them survive longer.

With the development of genetic engineering technology, CARs could be designed and transfected into T lymphocytes of patients by transfection in vitro.

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Currently, in vitro transfection technology can be divided into viral transduction and nonviral transfection, the former includes retrovirus and slow virus, whereas the latter includes transposon system and mRNA electrotransfection. However, due to the lack of assistance of costimulation molecules, CAR-T cells transfused into patients have poor proliferation and cannot get expected effects. Therefore, the ability of the second generation CAR-T cells to kill tumor cells is significantly improved.

Consequently, T cell proliferation activity and cytotoxicity as well as T cell survival are further improved. The addition of a proinflammatory factor such as IL12 and co-stimulatory molecule ligands 4—1 BBL and CD40L provides CAR-T cells with higher efficacy of killing tumor cells through the release of a proinflammatory factor. Note: Typical domain structures of the first to the fourth generation of CARs are shown. Currently, prostate-specific antigen PSA is the most common biomarker for prostate cancer.

As a glycoprotein composed of amino acids containing sugar chain, PSA is secreted by prostate gland vesicle and catheter epithelial cells with the activity of neutral serine protease and can be detected in the tissue, serum, and sperm. Because PSA has prostate tissue specificity, PSA is a good target to deliver drugs to tumor tissue to treat prostate cancer. However, due to serum PSA, avoiding the neutralization of targeted drugs and the side effects by serum PSA is still a difficult problem. Recent studies show that free prostate-specific antigen fPSA three hypotypes, namely benign prostate-specific antigen, inactive prostate-specific antigen, and precursor of PSA pro-PSA.

Among the three hypotypes of fPSA, pro-PSA has a higher expression in prostate cancer cells compared to the other two hypotypes, which makes it a more appropriate target for prostate cancer therapy.

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The prostate acid phosphatase PAP is another tumor marker for prostate cancer. Only after the prostate tissue is damaged, such as prostate cancer, a large amount of PAP will be released into the blood, which causes similar difficulty in the treatment of prostate cancer.


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PSMA expression is low in ovarian and breast cell membranes and almost absent in the intestines, liver, kidney cell membranes, but is high in prostate tissue and vessels of solid tumors, with the highest PSMA expression in semen. Furthermore, PSMA may function as a receptor to engage signaling to promote cell migration and regulate the stability of chromosomes. PSCA can be detected only on cell membrane since this antigen is not released into the blood.

The expression level of PSCA is positively correlated with tumor grade and clinical stage. It is important to note that healthy tissues that express the targeted antigen may subject to T cell-mediated damage. To solve this problem, Kloss et al came up with a strategy that T cells were transduced with both a CAR that provided suboptimal activation upon binding of one antigen and a chimeric costimulatory receptor that recognized a second antigen.