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Quest for Pan-Cancer Diagnosis/Prognosis Ends with HrC Test Measuring Oct4A in Peripheral Blood

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Abstract

Cancer is a devastating disease whose incidence has increased in recent times and early detection can lead to effective treatment. Existing detection tools suffer from low sensitivity and specificity, and are high cost, invasive and painful procedures. Cancers affecting different tissues, ubiquitously express embryonic markers including Oct-4A, whose expression levels have also been correlated to staging different types of cancer. Cancer stem cells (CSCs) that initiate cancer are possibly the ‘transformed’ and pluripotent very small embryonic-like stem cells (VSELs) that also express OCT-4A. Excessive self-renewal of otherwise quiescent, pluripotent VSELs in normal tissues possibly initiates cancer. In an initial study on 120 known cancer patients, it was observed that Oct-4A expression in peripheral blood correlated well with the stage of cancer. Based on these results, we developed a proprietary HrC scale wherein fold change of OCT-4A was linked to patient status – it is a numerical scoring system ranging from non-cancer (0–2), inflammation (>2–6), high-risk (>6–10), stage I (>10–20), stage II (>20–30), stage III (>30–40), and stage IV (>40) cancers. Later the scale was validated on 1000 subjects including 500 non-cancer and 500 cancer patients. Ten case studies are described and show (i) HrC scale can detect cancer, predict and monitor treatment outcome (ii) is superior to evaluating circulating tumor cells and (iii) can also serve as an early biomarker. HrC method is a novel breakthrough, non-invasive, blood-based diagnostic tool that can detect as well as classify solid tumors, hematological malignancies and sarcomas, based on their stage.

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References

  1. Clevers, H. (2011). The cancer stem cell: Premises, promises and challenges. Nature Medicine, 17(3), 313–319. https://doi.org/10.1038/nm.2304.

    Article  CAS  PubMed  Google Scholar 

  2. Batlle, E., & Clevers, H. (2017). Cancer stem cells revisited. Nature Medicine, 23, 1124–1134. https://doi.org/10.1038/nm.4409.

    Article  CAS  PubMed  Google Scholar 

  3. Ratajczak, M. Z., Ratajczak, J., & Kucia, M. (2019). Very small embryonic-like stem cells (VSELs): An update and future directions. Circulation Research, 124(2), 208–210. https://doi.org/10.1161/CIRCRESAHA.118.314287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bhartiya, D., Patel, H., Ganguly, R., Shaikh, A., Shukla, Y., Sharma, D., & Singh, P. (2018). Novel insights into adult and Cancer stem cell biology. Stem Cells and Development, 27(22), 1527–1539. https://doi.org/10.1089/scd.2018.0118.

    Article  PubMed  Google Scholar 

  5. Ratajczak, M. Z., Bujko, K., Mack, A., Kucia, M., & Ratajczak, J. (2019). Correction: Cancer from the perspective of stem cells and misappropriated tissue regeneration mechanisms (leukemia, (2018), 32, 12, (2519-2526), https://doi.org/10.1038/s41375-018-0294-7). Leukemia. https://doi.org/10.1038/s41375-019-0411-2.

  6. Ratajczak, M. Z., Shin, D.-M., & Kucia, M. (2009). Very small embryonic/epiblast-like stem cells. A missing link to support the germline hypothesis of cancer development? American Journal of Pathology, 174(6), 1985–1992.

    Article  CAS  Google Scholar 

  7. Ratajczak, M. Z., Shin, D.-M., Liu, R., Marlicz, W., Tarnowski, M., Ratajczak, J., & Kucia, M. (2010). Epiblast/germ line hypothesis of cancer development revisited: Lesson from the presence of Oct-4+ cells in adult tissues. Stem Cell Reviews and Reports, 6(2), 307–316.

    Article  Google Scholar 

  8. Kaushik, A., Anand, S., & Bhartiya, D. (2020). Altered biology of testicular VSELs and SSCs by neonatal endocrine disruption results in defective spermatogenesis, reduced fertility and tumor initiation in adult mice. Stem Cell Reviews and Reports, 16(5), 893–908. https://doi.org/10.1007/s12015-020-09996-3.

    Article  CAS  PubMed  Google Scholar 

  9. Virant-Klun, I., Skerl, P., Novakovic, S., Vrtacnik-Bokal, E., & Smrkolj, S. (2019). Similar population of CD133+ and DDX4+ VSEL-like stem cells sorted from human embryonic stem cell, ovarian, and ovarian Cancer ascites cell cultures: The real embryonic stem cells? Cells, 8(7), 706. https://doi.org/10.3390/cells8070706.

    Article  CAS  PubMed Central  Google Scholar 

  10. Samardzija, C., Luwor, R. B., Volchek, M., Quinn, M. A., Findlay, J. K., & Ahmed, N. (2015). A critical role of Oct4A in mediating metastasis and disease-free survival in a mouse model of ovarian cancer. Molecular Cancer, 14(1), 152. https://doi.org/10.1186/s12943-015-0417-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhao, X., Lu, H., Sun, Y., Liu, L., & Wang, H. (2020). Prognostic value of octamer binding transcription factor 4 for patients with solid tumors: A meta-analysis. Medicine, 99(42), e22804. https://doi.org/10.1097/MD.0000000000022804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bhartiya, D., Shaikh, A., Nagvenkar, P., Kasiviswanathan, S., Pethe, P., Pawani, H., Mohanty, S., Rao, S. G. A., Zaveri, K., & Hinduja, I. (2012). Very small embryonic-like stem cells with maximum regenerative potential get discarded during cord blood banking and bone marrow processing for autologous stem cell therapy. Stem Cells and Development, 21(1), 1–6. https://doi.org/10.1089/scd.2011.0311.

    Article  CAS  PubMed  Google Scholar 

  13. Singh, P., & Bhartiya, D. (2020). Pluripotent stem (VSELs) and progenitor (EnSCs) cells exist in adult mouse uterus and show cyclic changes across estrus cycle. Reproductive Sciences, 28(1), 278–290. https://doi.org/10.1007/s43032-020-00250-2.

    Article  CAS  PubMed  Google Scholar 

  14. Palmirotta, R., Lovero, D., Cafforio, P., Felici, C., Mannavola, F., Pellè, E., Quaresmini, D., Tucci, M., & Silvestris, F. (2018). Liquid biopsy of cancer: A multimodal diagnostic tool in clinical oncology. Therapeutic Advances in Medical Oncology, 10, 175883591879463. https://doi.org/10.1177/1758835918794630.

    Article  Google Scholar 

  15. Diehl, F., Schmidt, K., Choti, M. A., Romans, K., Goodman, S., Li, M., et al. (2008). Circulating mutant DNA to assess tumor dynamics. Nature Medicine, 14(9), 985–990. https://doi.org/10.1038/nm.1789.

    Article  CAS  PubMed  Google Scholar 

  16. Wagner, M., Yoshihara, M., Douagi, I., Damdimopoulos, A., Panula, S., Petropoulos, S., Lu, H., Pettersson, K., Palm, K., Katayama, S., Hovatta, O., Kere, J., Lanner, F., & Damdimopoulou, P. (2020). Single-cell analysis of human ovarian cortex identifies distinct cell populations but no oogonial stem cells. Nature Communications, 11(1), 1147. https://doi.org/10.1038/s41467-020-14936-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Karthaus, W. R., Hofree, M., Choi, D., Linton, E. L., Turkekul, M., Bejnood, A., Carver, B., Gopalan, A., Abida, W., Laudone, V., Biton, M., Chaudhary, O., Xu, T., Masilionis, I., Manova, K., Mazutis, L., Pe’er, D., Regev, A., & Sawyers, C. L. (2020). Regenerative potential of prostate luminal cells revealed by single-cell analysis. Science, 368(6490), 497–505. https://doi.org/10.1126/science.aay0267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bhartiya, D., & Sharma, D. (2020). Ovary does harbor stem cells-size of the cells matter! Journal of Ovarian Research, 13(1), 39. https://doi.org/10.1186/s13048-020-00647-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mohammad, S. A., Metkari, S., & Bhartiya, D. (2020). Mouse pancreas stem/progenitor cells get augmented by Streptozotocin and regenerate diabetic pancreas after partial Pancreatectomy. Stem Cell Reviews and Reports, 16(1), 144–158. https://doi.org/10.1007/s12015-019-09919-x.

    Article  PubMed  Google Scholar 

  20. Kaushik, A., & Bhartiya, D. (2020). Additional evidence to establish existence of two stem cell populations including VSELs and SSCs in adult mouse testes. Stem Cell Reviews and Reports, 16(5), 992–1004. https://doi.org/10.1007/s12015-020-09993-6.

    Article  CAS  PubMed  Google Scholar 

  21. Shaikh, A., Anand, S., Kapoor, S., Ganguly, R., & Bhartiya, D. (2017). Mouse bone marrow VSELs exhibit differentiation into three embryonic germ lineages and Germ & Hematopoietic Cells in culture. Stem Cell Reviews and Reports, 13(2), 202–216. https://doi.org/10.1007/s12015-016-9714-0.

    Article  CAS  PubMed  Google Scholar 

  22. Shin, D. M., Zuba-Surma, E. K., Wu, W., Ratajczak, J., Wysoczynski, M., Ratajczak, M. Z., & Kucia, M. (2009). Novel epigenetic mechanisms that control pluripotency and quiescence of adult bone marrow-derived Oct4+ very small embryonic-like stem cells. Leukemia, 23(11), 2042–2051. https://doi.org/10.1038/leu.2009.153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bhartiya, D., Anand, S., Kaushik, A., & Sharma, D. (2019). Stem cells in the mammalian gonads. Advances in Experimental Medicine and Biology, 1201, 109–123.

    Article  CAS  Google Scholar 

  24. Crowley, E., Di Nicolantonio, F., Loupakis, F., & Bardelli, A. (2013). Liquid biopsy: Monitoring cancer-genetics in the blood. Nature Reviews Clinical Oncology, 10(8), 472–484. https://doi.org/10.1038/nrclinonc.2013.110.

    Article  CAS  PubMed  Google Scholar 

  25. Shyamala, K., Girish, H., & Murgod, S. (2014). Risk of tumor cell seeding through biopsy and aspiration cytology. Journal of International Society of Preventive and Community Dentistry, 4(1), 5–11. https://doi.org/10.4103/2231-0762.129446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Robertson, E. G., & Baxter, G. (2011). Tumour seeding following percutaneous needle biopsy: The real story! Clinical Radiology, 66(11), 1007–1014. https://doi.org/10.1016/j.crad.2011.05.012.

    Article  CAS  PubMed  Google Scholar 

  27. Holder, A. M., & Varadhachary, G. R. (2018). Cancer of unknown primary site. The MD Anderson Surgical Oncology Handbook, Sixth Edition, 44(9), 613–626.

    Google Scholar 

  28. Hawkey N.M., & Armstrong A.J. (2021). Liquid biopsy: It’s the bloody truth!. Clinical Cancer Research., clincanres.0531.2021

  29. Yu, W., Hurley, J., Roberts, D., Chakrabortty, S. K., Enderle, D., Noerholm, M., Breakefield, X. O., & Skog, J. K. (2021). Exosome-based liquid biopsies in cancer: Opportunities and challenges. Annals of Oncology, 32(4), 466–477.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge Dr. AnantBhushan Ranade, Dr. Amit Bhatt and Dr. Rucha Dasare from Avinash Cancer Clinic for their generous support and for aiding in designing the clinical trial.

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Authors and Affiliations

  1. Epigeneres Biotech Pvt Ltd., C-701, Ganpatrao Kadam Marg, Lower Parel, Mumbai, 400013, India

    VinayKumar Tripathi, Sagar Chhabria, Nripen Sharma, Bipin Chand, Vaishnavi Takle & Ashish Tripathi

  2. ICMR - National Institute for Research in Reproductive Health, J Merwanji Street, Parel East, Parel, Mumbai, Maharashtra, 400012, India

    Deepa Bhartiya

  3. Medanta Hospital, CH Baktawar Singh Road, Sector 38, Gurugram, Haryana, 122001, India

    Ashok Vaid

  4. National Facility for Biopharmaceuticals, Road Number 32, Matunga, Mumbai, 400019, India

    Pratiksha Palahe

  5. 23Ikigai Pte Ltd., 30 Cecil Street, #21-08 Prudential Tower, Singapore, 049712, Singapore

    Ashish Tripathi

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  1. VinayKumar Tripathi
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Contributions

AR, AB and RD recruited subjects and reviewed the paper. DB wrote sections of the paper and reviewed it. VKT, AV and PP reviewed the paper. SC, VT performed laboratory experiments, analysed the data and reviewed the paper. NS reviewed the paper and drafted sections. BC performed statistical analysis. AT wrote sections as well as reviewed the paper.

Corresponding author

Correspondence to Ashish Tripathi.

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Ethics Approval

Ethics approval from Ethics Committee of Maharashtra Technical Education Society at Sanjeevan Hospital, Pune, India and was registered with Clinical Trial Registry India (CTRI/2019/01/017166).

Consent to Participate

Informed consent was obtained from all individual participants included in the study.

Consent for Publication

Patients signed informed consent regarding publishing their data.

Conflict of Interest

The HrC scale was co-developed by Epigeneres Biotech. The pilot clinical study was sponsored by Epigeneres Biotech. The IP for the technology is owned by 23Ikigai.

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Highlights

• Cancers ubiquitously express embryonic marker Oct-4A, whose expression levels are related to stages of cancer.

• Cancer is initiated by the excessive self-renewal of very small embryonic-like stem cells (VSELs) that express Oct-4A.

• We developed a proprietary HrC scale wherein fold change of OCT-4A was linked to patient status.

• HrC scale can effectively screen, diagnose and prognose cancer with 100% sensitivity and specificity.

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Tripathi, V., Bhartiya, D., Vaid, A. et al. Quest for Pan-Cancer Diagnosis/Prognosis Ends with HrC Test Measuring Oct4A in Peripheral Blood. Stem Cell Rev and Rep 17, 1827–1839 (2021). https://doi.org/10.1007/s12015-021-10167-1

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