THE ROLE OF HEMOGLOBIN IN CANCER – AN OPINION (ISSN 2753-8176 (online), DOI:10.13140/RG.2.2.17696.97281)

THE ROLE OF HEMOGLOBIN IN CANCER – AN OPINION

ISSN 2753-8176 (online), DOI:10.13140/RG.2.2.17696.97281

Ana Pedro1

1Gwyntwr1386 Pharmacy, Regus Chester Business Park, Heronsway, Chester, CH49QR, UK

We have identified by proteomics analysis a possible biomarker for early stage ER+ breast cancer (BC), HCG1745306 isoform CRA-a, an isoform of haemoglobin subunit alpha (HBA) (1). A large body of evidence supports a role for haemoglobin not only in BC diagnosis but also in cancer diagnosis in general. HBA has also been previously found to be upregulated in the urine of patients with early invasive BC (2). Also, previous work indicated the possibility of a direct relationship between the hemoglobin level and not only the early stages of cancer, but also the chemically induced precancerous condition (3).

Total haemoglobin (THC) has been shown to be present in higher concentrations in breast tumours in comparison to healthy tissues while oxyhemoglobin has been showed to be reduced thus reflecting early metabolic changes in cancer towards hypoxia (4,5). Haemoglobin has also been shown to predict axillary staging with a multivariate analysis study showing an independent relationship between the probability of axillary metastasis and elevated THC (6) .THC is significantly correlated with prognostic factors such as tumor size, histologic grade, ER, PR, and c-erbB-2 (7). In particular, hemoglobin beta expression (HBB) increases BC cells aggressiveness and associates with poor prognosis (8). In addition, in triple-negative BC, low hemoglobin is significantly associated with decreased disease-free survival (DFS) and overall survival (OS) (9). Low pretreatment haemoglobin levels may also negatively influence the tumour response to primary chemotherapy in BC (10). Anaemia during adjuvant chemotherapy is also associated with poor survival in patients with primary BC (11, 12).Blood hemoglobin concentration also seems to affect the prognosis of patients with early BC when a treatment schedule that includes radiotherapy is applied. Reduced radiosensitivity due to diminished tumor oxygenation may be the underlying cause (13). Also, in patients with a diagnosis of primary lung, colorectal, breast or liver cancer, higher post-diagnosis haemoglobin change regardless of the baseline haemoglobin levels and the direction of changes associates with a significantly shorter survival(14).

Moreover, different hemoglobin subtypes are expressed in samples derived from patients (including tumor samples) with different types of tumor and tumor cell lines derived from different types of tumors indicating that hemoglobin can be derived from the tumors (15) and the variation in the distribution of these hemoglobin subtypes seems to correlated in certain instances with tumor progression stages (16-24). Curiously, P53 overexpression in colorectal cancer (CRC) causes a decrease in the scores of HBB and HBA in primary CRC cell lines. In stage III there are decreases in the scores of HBB and HBA. As in stage III there are decreases in the scores of HBB and HBA, perhaps this explains the efficacy of adjuvant chemotherapy at this stage (25).

By other side, it was suggested that both diabetes and/or elevated glycated hemoglobin (HbA1c) are associated with risk of cancer at several anatomic sites (26). Indeed, in hypoxic conditions, cancer cell metabolism undergoes a shift from oxidative phosphorylation to aerobic glycolysis (27). Indeed, tumor-derived hemoglobin might promote tumor cell survival. In a study was found that metastasis-competent circulating tumour cells (CTCs) experience oxidative stress in the bloodstream, although their survival mechanisms are not well defined. In CTCs from breast, prostate and lung cancers, there is consistent induction of HBB . The tumour-specific origin of HBB was confirmed by sequence polymorphisms within human xenograft-derived CTCs in mouse models. Increased intracellular reactive oxygen species (ROS) in cultured breast CTCs triggered HBB induction suggesting that HBB is selectively deregulated in cancer cells, mediating a cytoprotective effect during blood-borne metastasis (28).

In conclusion:

- THC and different hemoglobin subunits seem to be associated with cancer progression and response to cancer treatment

- Hypoxia also seem to be associated with cancer progression and response to cancer treatment

- HBB seems to increase cancer cell aggressiveness

- HbA1c seems to be related with cancer, which might be related with cancer cell metabolic shift through a mechanism not very well defined

- Hemoglobin can be tumor - derived and might be selectively deregulated to promote cancer cell survival

References:

1. Tucker R,Pedro A. Blood-derived non-extracellular vesicle proteins as potential biomarkers for the diagnosis of early ER+ breast cancer and detection of lymph node involvement. Version 3.F1000Res.2018 Mar 6 [revised 2018 May 10];7:283. doi: 10.12688/f1000research.14129.3. eCollection 2018.

2.Beretov J,Wasinger VC,Millar EK,Schwartz P,Graham PH, Li Y.Proteomic Analysis of Urine to Identify Breast Cancer Biomarker Candidates Using a Label-Free LC-MS/MS Approach.PLoS One.2015 Nov 6;10(11):e0141876. doi: 10.1371/journal.pone.0141876.

3. Taylor A, Pollack, MA. Hemoglobin Level and Tumor Growth. Cancer Research (1942)

4.Anderson PG, Kainerstorfer JM, Sassaroli A, Krishnamurthy N,Homer MJ,Graham RA,Fantini S.Broadband optical mammography: chromophore concentration and hemoglobin saturation contrast in breast cancer.PLoS One.2015 Mar 17;10(3):e0117322.

5. Phys Med Biol. 2004 Apr 7;49(7):1165-81.Concentration and oxygen saturation of haemoglobin of 50 breast tumours determined by time-domain optical mammography. Grosenick D1, Wabnitz H, Moesta KT,Mucke J,Möller M, Stroszczynski C,Stössel J, Wassermann B,Schlag PM,Rinneberg H.

6.Eur J Radiol.2012 Nov;81(11):3185-9. doi: 10.1016/j.ejrad.2012.01.029. Epub 2012 Mar 7. Ultrasound-guided diffuse optical tomography (DOT) of invasive breast carcinoma: does tumour total haemoglobin concentration contribute to the prediction of axillary lymph node status? Zhu Q1, Xiao M,You S, Zhang J, Jiang Y, Lai X, Dai Q.

7. Acad Radiol. 2015 Apr;22(4):439-46. doi: 10.1016/j.acra.2014.12.012. Diffuse optical tomography of breast carcinoma: can tumor total hemoglobin concentration be considered as a new promising prognostic parameter of breast carcinoma? Xiao M, Jiang Y, Zhu Q, You S, Li J, Wang H, Lai X, Zhang J, Liu H, Zhang J.

8. Non-conventional role of haemoglobin beta in breast malignancy. British Journal of Cancer (2017) 117, 994–1006 | doi: 10.1038/bjc.2017.247. Marco Ponzetti

9. PLoS One.2016 Nov 16;11(11):e0165133. doi: 10.1371/journal.pone.0165133. eCollection 2016.Pretreatment Hematocrit Is Superior to Hemoglobin as a Prognostic Factor for Triple Negative Breast

10. Br J Cancer. 2003 Sep 15;89(6):977-82. Pretreatment haemoglobin levels significantly predict the tumour response to primary chemotherapy in human breast cancer. Bottini A1, Berruti A, Brizzi MP, Bersiga A, Generali D, Allevi G, Aguggini S, Bolsi G, Bonardi S, Bertoli G, Alquati P,Dogliotti L.

11.Impact of haemoglobin levels during adjuvant chemotherapy on the survival of patients with primary breast cancer. Peters-Engl C, Cassik P, Schmidt I, Denison U, Medl M, Pokieser W, Sevelda P.

12.Anticancer Res.2007 Mar-Apr;27(2):1223-6.Prognostic impact of haemoglobin levels in breast cancer.

13. Strahlenther Onkol. 2004 Jan;180(1):45-51. Blood hemoglobin level and treatment outcome of early breast cancer. Henke M, Sindlinger F, Ikenberg H, Gerds T, Schumacher M.

14.BMC Cancer. 2013 Jul 10;13:340. doi: 10.1186/1471-2407-13-340.Post-diagnosis hemoglobin change associates with overall survival of multiple malignancies - results from a 14-year hospital-based cohort of lung, breast, colorectal, and liver cancers. Wan S, Lai Y, Myers RE, Li B, Palazzo JP, Burkart AL, Chen G, Xing J, Yang H.

15. Pedro A (2023). A Review of The Role of Hemoglobin in Different types of Cancer ISSN 2753-8176 (online), DOI:10.13140/RG.2.2.24610.20164

16. Pedro A (2022). Hemoglobin as a biomarker for breast cancer ISSN 2753-8176 (online) (DOI: 10.13140/RG.2.2.25461.65764)

17. Pedro A (2022). Hemoglobin as a biomarker for melanoma - short report DOI: 10.13140/RG.2.2.32520.29445, ISSN 2753-8176 (online)

18. Pedro A (2022). Hemoglobin in colorectal cancer (DOI: 10.13140/RG.2.2.32515.99363, ISSN 2753-8176 (online))

19. Pedro A (2023).Hemoglobin in gastric cancer (ISSN 2753-8176 (online), DOI:10.1101/202291v1 , Small report

20. Pedro A (2023).Hemoglobin in Lung Cancer - Short report (ISSN 2753-8176 (online), DOI: 10.13140/RG.2.2.30186.59842

21.Pedro A (2023).Hemoglobin in Head and Neck cancer - Short report (ISSN 2753-8176 (online), DOI: 10.13140/RG.2.2.16792.67846

22. Pedro A (2023).Hemoglobin and osteoblasts markers in bone cancer, ISSN 2753-8176 (online), DOI: 10.13140/RG.2.2.14509.05606

23. Pedro A (2023).Hemoglobin and Children’s cancers - Brief Report, DOI: 10.13140/RG.2.2.21321.52325, ISSN 2753-8176 (online)

24. Pedro A (2023).Hemoglobin in Acute Leukemias - Brief report , ISSN 2753-8176 (online)

25. Pedro A (2023). Therapy with DNA damaging drugs of a small number of non-metastatic and metastatic colorectal cancer patients ISSN 2753-8176 (online)

26. Peila and Rohan (2020). Diabetes, Glycated Hemoglobin, and Risk of Cancer in the UK Biobank Study

27. Tameemi et al (2019). Hypoxia-Modified Cancer Cell Metabolism.Front Cell Dev Biol.; 7: 4.

28. Zheng et al (2017). Expression of β-globin by cancer cells promotes cell survival during blood-borne dissemination.Nature Communications 8, Article number: 14344

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