DETECTION OF DISSEMINATED TUMOR CELLS IN THE BONE MARROW OF PATIENTS WITH NON-SMALL CELL LUNG CANCER
S. V. Chulkova,
N. N. Tupitsyn,
T. M. Djumanazarov,
A. D. Palladina,
N. A. Kupryshina,
O. A. Chernysheva,
A. K. Allakhverdiev,
O. P. Kolbatskaya,
P. V. Kononetz https://doi.org/10.17650/1726-9784-2020-19-3-29-37
Abstract
Introduction. There is evidence that disseminated tumor cells (DOCs) in the bone marrow (BM) are precursors of subsequent distant metastases. The detection of DOCs in non-small cell lung cancer (NSCLC) will provide important information about the features of metastasis, as well as the possibilities of identifying new targets for the treatment of NSCLC.
Purpose of the study is to evaluate the possibility of detection DOCs in BM and to identify the frequency of BM involvement in patients with NSCLC.
Materials and methods. Morphological and immunological methods studied 62 BM samples from patients with NSCLC. DOCs analysis was performed using flow cytometry (FACSCanto II, USA, Kaluza Analysis v 2.1 software), monoclonal antibodies to CD45, cytokeratins directly labeled with various fluorochromes were used.
Results. DOCs (EPCAM+CD45–) in the BM were found in 43.5 % of patients (threshold level: 1 cell per 10 million myelocaricytes). The presence of DOCs did not correlate with tumor size, lymph node status, stage of the tumor process. The highest detection rates of DOCs were observed at stages IA and IIA: 60.7 % (3/5) and 58.3 % (7/12) respectively. BM involvement in adenocarcinoma was observed in 45 % (15/33) cases, in squamous cell carcinoma – in 37 % (10/27) samples (p = 0.501). It was found that DOCs are more often detected in more differentiated tumors (p = 0.023). Significant correlations between the presence of DOCs in the BM and myelogram parameters have not been established. A decrease in the number of granulocyte germ cells was observed in 4 % of BM involvement (p = 0.036).
Conclusion. The possibility of detecting DOCs in the BM of NSCLC patients has been established. BM involvement was 43.5 %. DOCs are detected even in the early stages of NSCLC. Relationship between BM involvement and the degree of tumor differentiation was found. More frequent BM involvement was observed in adenocarcinoma compared with squamous cell carcinoma of the lung.
Compliance with patient rights and principles of bioethics
The study protocol was approved by the biomedical ethics committee of N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia. All patients gave written informed consent to participate in the study.
About the Authors
S. V. Chulkova
N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia;
N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia
Russian Federation
Russian Federation
N. N. Tupitsyn
N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia
Russian Federation
Russian Federation
T. M. Djumanazarov
N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia
Russian Federation
Russian Federation
A. D. Palladina
N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia
Russian Federation
Russian Federation
N. A. Kupryshina
N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia
Russian Federation
Russian Federation
O. A. Chernysheva
N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia
Russian Federation
Russian Federation
A. K. Allakhverdiev
Moscow Clinical Scientific and Practical Center of Moscow Department of Healthcare;
Russian Medical Academy of Continuous Professional Education of the Ministry of Health of Russia
Russian Federation
Russian Federation
O. P. Kolbatskaya
N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia
Russian Federation
Russian Federation
P. V. Kononetz
N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia
Russian Federation
Russian Federation
References
1. American Cancer Society. Cancer Fact and Figures. 2018.
2. Sai B., Xiang J. Disseminated tumor cells in bone marrow are the source of cancer relapse after therapy. J Cell Mol Med 2018;22:5776–86. DOI: 10.1111/jcmm.13867.
3. Pein M., Hongu T., Riedel A. et al. Metastasis-initiating cells induce and exploit a fibroblast niche to fuel malignant colonization of the lungs. Nat Commun 2020;11(1):1494. DOI: 10.1038/s41467-020-15188-x.
4. Markina I.G., Tupitsyn N.N., Mikhailova I.N., Demidov L.V. Hematogenous tumor metastasis: key points and evolving paradigms. Immunologiya gemopoeza = Hematopoiesis Immunology 2018;6(1):109–32. (In Russ.).
5. Tupitsyn N.N. Bone marrow of a cancer patient: staging of tumors, hematopoiesis, immune system. Immunologiya gemopoeza = Hematopoiesis Immunology 2018;16(2):10–54. (In Russ.).
6. Ryabchikov D.A., Beznos O.A., Dudina I.A. et al. Disseminated tumor cells in patients with luminal breast cancer. Rossiyskiy bioterapevticheskiy zhurnal = Russian Biotherapeutic Journal 2018;17(1):53–7. (In Russ.).
7. Chernysheva O., Markina I., Demidov L. et al. Bone marrow involvement in melanoma. Potentials for detection of disseminated tumor cells and characterization of their subsets by flow cytometry. Cells 2019;8(6):627.DOI: 10.3390/cells8060627.
8. Pantel K., Alix-Panabieres C. Bone marrow as a reservoir for disseminated tumor cells: a special source for liquid biopsy in cancer patients. Bonekey Rep 2014;3:584. DOI: 10.1038/bonekey.2014.79.
9. Dasgupta A., Lim A.R., Ghajar C.M. Circulating and disseminated tumor cells: harbingers or initiators of metastasis? Mol Oncol 2017;11:40–61. DOI: 10.1002/1878-0261.12022.
10. Zarrer J., Haider M.-T., Daniel J. et al. Pathological crosstalk between metastatic breast cancer cells and the bone microenvironment. Biomolecules 2020;10(2):337. DOI: 10.3390/biom10020337.
11. Price T.T., Burness M.L., Sivan A. et al. Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone. Sci Transl Med 2016;8(340):340ra73. DOI: 10.1126/scitranslmed.aad4059.
12. Klein C.A. Parallel progression of primary tumours and metastases. Nat Rev Cancer 2009;9(4):302–12. DOI: 10.1038/nrc2627.
13. Demeulemeester J., Kumar P., Møller E.K. et al. Tracing the origin of disseminated tumor cells in breast cancer using single‐cell sequencing. Genome Biol 2016;17:250. DOI: 10.1186/s13059-016-1109-7.
14. Foulds L. The natural history of cancer. J Chronic Dis 1958;8(1):2–37. DOI: 10.1016/0021-9681(58)90039-0.
15. Tupitsyn N.N. Circulating and disseminated tumor cells in breast cancer and ovarian cancer. Onkoginekologiya = Oncogynecology 2013;(1):12–8. (In Russ.).
16. Besova N.S., Obarevich E.S., Davydov M.M. et al. The prognostic value of disseminated tumor cells in the bone marrow of patients with disseminated gastric cancer before the start of antitumor therapy. Farmateka 2017;17(350):62–6. (In Russ.).
17. Mohme M., Riethdorf S., Pantel K. Circulating and disseminated tumour cells – mechanisms of immune surveillance and escape. Nat Rev Clin Oncol 2017;14(3):155–67. DOI: 10.1038/nrclinonc.2016.144.
18. Ghajar C.M. Metastasis prevention by targeting the dormant niche. Nat Rev Cancer 2015;15(4):238–47. DOI: 10.1038/nrc3910.
19. Nicolini A., Rossi G., Ferrari P., Carpi A. Minimal residual disease in advanced or metastatic solid cancers: the G0–G1 state and immunotherapy are key to unwinding cancer complexity. Semin Cancer Biol 2020;S1044–579X(20):30075–4. DOI: 10.1016/j.semcancer.2020.03.009.
20. Tupitsyn N.N., Mkrtchan V.A., Palladina A.D. et al. Bone marrow lymphocyte populations of innate immunity in breast cancer patients. GJMR-F 2020;20(2):20–2.
21. Sienel W., Mecklenburg I., Dango S. et al. Detection of MAGE-A transcripts in bone marrow is an independent prognostic factor in operable non-smallcell lung cancer. Clin Cancer Res 2007;13(13):3840–7. DOI: 10.1158/1078-0432.CCR-06-2507.
22. Johnson R.W., Finger E.C., Olcina M.M. et al. Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow. Nat Cell Biol 2016;18(10):1078–89. DOI: 10.1038/ncb3408.
Review
For citations:
Chulkova S.V., Tupitsyn N.N., Djumanazarov T.M., Palladina A.D., Kupryshina N.A., Chernysheva O.A., Allakhverdiev A.K., Kolbatskaya O.P., Kononetz P.V. DETECTION OF DISSEMINATED TUMOR CELLS IN THE BONE MARROW OF PATIENTS WITH NON-SMALL CELL LUNG CANCER. Russian Journal of Biotherapy. 2020;19(3):29-37. (In Russ.) https://doi.org/10.17650/1726-9784-2020-19-3-29-37
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