Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Dec 15;17(1):1641-1656.
doi: 10.1515/biol-2022-0102. eCollection 2022.

The role of erythrocytes and erythroid progenitor cells in tumors

Hao Zhang  1   2   3 , Guang-Zhi Wan  2 , Yu-Ying Wang  4 , Wen Chen  5 , Jing-Zhi Guan  2
Affiliations
Review

The role of erythrocytes and erythroid progenitor cells in tumors

Hao Zhang et al. Open Life Sci. .

Abstract

In the current research context of precision treatment of malignant tumors, the advantages of immunotherapy are unmatched by conventional antitumor therapy, which can prolong progression-free survival and overall survival. The search for new targets and novel combination therapies can improve the efficacy of immunotherapy and reduce adverse effects. Since current research targets for immunotherapy mainly focus on lymphocytes, little research has been done on erythrocytes. Nucleated erythroid precursor stem cells have been discovered to play an essential role in tumor progression. Researchers are exploring new targets and therapeutic approaches for immunotherapy from the perspective of erythroid progenitor cells (EPCs). Recent studies have shown that different subtypes of EPCs have specific surface markers and distinct biological roles in tumor immunity. CD45+ EPCs are potent myeloid-derived suppressor cell-like immunosuppressants that reduce the patient's antitumor immune response. CD45- EPCs promote tumor invasion and metastasis by secreting artemin. A specific type of EPC also promotes angiogenesis and provides radiation protection. Therefore, EPCs may be involved in tumor growth, infiltration, and metastasis. It may also be an important cause of anti-angiogenesis and immunotherapy resistance. This review summarizes recent research advances in erythropoiesis, EPC features, and their impacts and processes on tumors.

Keywords: EPCs; anemia; erythroid progenitor cells; immunotherapy; tumor.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: Authors state no conflict of interest.

Figures

Figure 1
Figure 1
Primary mechanisms of erythrocyte-mediated immunity: (1) NKEF in erythrocyte cytoplasm enhances the killing ability of NK-cells; (2) erythrocytes with CD47 unbound anti-CD47 mAb show apoptosis; (3) CD58 on the erythrocyte membrane can interact with CD2 on the lymphocyte membrane, thus inducing cytokine production by T lymphocytes and promoting the proliferation and differentiation of B lymphocytes; (4) erythrocytes complete IAC through CR1 binding to C3b; (5) erythrocytes in healthy humans can promote T-lymphocyte proliferation; (6) antioxidants contained in erythrocytes increase phagocytosis; (7) signal regulatory protein α interacts with CD47 to also promote phagocytosis of apoptotic cells [23]; and (8) erythrocytes expressed DARC can bind and scavenge cytokines released by tumor cells.
Figure 2
Figure 2
The role of EPCs in cancer. (1) Tumors promote the expansion of EPCs and (2) tumors inhibit the maturation and differentiation of EPCs. Early CD45+ EPCs use (a) TGF-β, (b) ROS, (c) IL-10 and (d) PD-L1 regulates immune responses. More mature CD45− EPCs regulate cancer progression through (e) secretion of Artemin.
Figure 3
Figure 3
The role of EPCs n cancer. CD45+ EPCs inhibit (1) T-cell proliferation, (2) T-cell activation, (3) IFN-γ and TNF-α production, and (4) CD8+ T-cell cytotoxicity. CD45− EPCs promote (5) tumor cell metastasis and invasion and (6) tumor growth and cell proliferation.
Figure 4
Figure 4
The main pathways and molecules involved in regulating erythropoiesis. The different stages are shown: HSC, BFU-E, CFU-E, Pro-E, Baso-E, Poly-E, Ortho-E, and erythrocytes. Molecules involved: zinc finger factors that bind GATA sequences (GATA-1, GATA-2); IL-3; IL-3-R; SCF; c-Kit; EPO; EPO-R; Ter-119, glycophorin A-associated protein; CD235a, glycophorin A; CD44, cell surface adhesion molecule; CD34, transmembrane phosphoglycoprotein; CD36, platelet glycoprotein protein 4; CD45, common marker of leukocytes; BCL-xL, anti-apoptotic protein; hemoglobin; FAS; FAS-L; Tf; TfR-1 (or CD71), transferrin receptor 1; TGF-β; activin A; BMP-2, bone morphogenetic protein 2; GDF, growth differentiation factor. Vitamins, trace elements, and iron metabolism proteins necessary for erythropoiesis: vitamin B12, folic acid, copper, iron, ferritin, ferroprotin, hepcidin).
Figure 5
Figure 5
Critical modulations that promote differentiation of erythroid progenitors: (a) inhibition of TGF-β and (b) binding of GDF11 via ACE-536 effectively rescued differentiation arrest of EPCs; (c) EPO and (d) Bmi1 enhanced differentiation of EPCs; (e) iron, folic acid, and vitamin C also promoted differentiation of EPCs; (f) antagonism of AHR signaling improved hESC-derived erythrocyte production and enhanced terminal differentiation of EPCs; (g) caspase-1 promotes differentiation of EPCs by cleaving GATA1; (h) inhibition of mTOR signaling enhances maturation of EPCs; (i) inhibition of Notch signaling by GSI induces differentiation of EPCs and promotes hemoglobin production; (j) E2F-2 is expressed at high levels in (k). GATA-1 is essential for the differentiation and maturation of late EPCs; (l) hypoxia increases the expression of GATA-1 protein, and overexpression of GATA-1 increases the level of HIF-1α, which promotes the differentiation and maturation of EPCs; and (m) enhanced EKLF in late EKLF of EPCs may promote differentiation of terminal red lineage cells [161,162].
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Bejarano L, Jordāo MJC, Joyce JA. Therapeutic targeting of the tumor microenvironment. Cancer Discov. 2021 Apr;11(4):933–59. - PubMed
    1. Tang T, Huang X, Zhang G, Hong Z, Bai X, Liang T. Advantages of targeting the tumor immune microenvironment over blocking immune checkpoint in cancer immunotherapy. Signal Transduct Target Ther. 2021 Feb 20;6(1):72. - PMC - PubMed
    1. Tarin D. Clinical and biological implications of the tumor microenvironment. Cancer Microenviron. 2012 Feb 3;5(2):95–112. - PMC - PubMed
    1. Chen F, Zhuang X, Lin L, Yu P, Wang Y, Shi Y, et al. New horizons in tumor microenvironment biology: challenges and opportunities. BMC Med. 2015 Mar 5;13:45. - PMC - PubMed
    1. Chen J, Qiao YD, Li X, Xu JL, Ye QJ, Jiang N, et al. Intratumoral CD45+CD71+ erythroid cells induce immune tolerance and predict tumor recurrence in hepatocellular carcinoma. Cancer Lett. 2021 Feb 28;499:85–98. - PubMed

LinkOut - more resources