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The Role of A2M in Cancer – a review (ISSN 2753-8176 (online))

1.Ana Pedro

1.Gwyntwr1386 CIC, U.K.

info@gwyntwr1386.com

Introduction

Alpha-2-macroglobulin (α2M) is a large protein found in the blood which is mainly produced by the liver. α2M is the largest major non-immunoglobulin protein in human plasma (1).

It functions as a broad-spectrum protease inhibitor which are involved in various biological processes such as inflammation, cell growth, and blood clotting (2). α2M can also bind to and regulate cytokines and growth factors, thus influencing the immune system response (3). α2M also may play a role in various cancers and has been implicated in the development of some cancers and also as a tumor suppressor in other cancer types (4). α2M may act as an anticancer agent by inhibiting proteases, which are enzymes that can promote tumor growth and metastasis. It can also bind to and neutralize growth factors and cytokines, potentially slowing down cancer cell proliferation (5). However, α2M may also promote tumor growth and metastasis by interacting with other molecules like LRP1 (Low Density Lipoprotein Receptor-related Protein 1) (6). Studies suggest that α2M levels might be altered in various cancer types, potentially making it a useful biomarker for diagnosis and prognosis (7).

Here, we summarize the role of A2M in different types of cancer.

Breast cancer

We found out that α2M had a huge score in female 2, 1, male 1 and CF110 samples (tables 1 and 2). By comparing controls samples, female 1, female 2 and male 2 with early cancer patient CF5 and CF27 samples, we can see that these control samples have much bigger α2M scores than the mentioned cancer samples, while male 1 control sample seems to have a smaller score than all the control and cancer samples except for samples CF5 and CF1. This suggests that high levels of α2M in controls might be related with cancer development. Also, sample CF110 has a bigger α2M score than samples CF37 and CF5, suggesting than cancer progression might be related with higher α2M levels. Finally, samples CF1, CF25, CF27 and CF33 show progressive bigger α2M scores suggesting once again bigger α2M might be related with cancer progression (8).

Melanoma

We found out (Table 3 and fig.1 ) that A2M score in lymphatic fluid (LF) control 2 is much bigger than in LF control 1 so might control 2 be prone to develop cancer? Also, when we analyze LF samples from melanoma with only lymph node (LN) metastasis (fig1.), we found out that sample 9 has a small A2M score (smaller than control 1), while sample 7 does not show any A2M at all. Moreover, sample 10 shows quite a good A2M score (bigger than the one for control 1 although smaller than control 2). Will sample 10, progress to metastatic melanoma while samples 9 and 7 will not? Finally, metastic melanona samples 5, 2 and 3 present A2M with scores smaller than sample 10 and control 2. Moreover among these metastatic samples, sample 2 (subcutaneous metastasis) is the one who presents a bigger A2M score. Will sample 2 progress for more far distant metastases? Will samples 5 and 3 end up their metastatic journey? (9)

Pancreatic cancer

In table 4, we analyzed A2M Mascot scores for two different mouse normal pancreas tissue CM (conditioned media) samples (one shows a significant Mascot Score, while the other shows no A2M), PanIn cell line CM samples (precursor to invasive ductal cell adenocarcinoma, precancerous), Pan02 (mouse adenocarcinoma cell line) CM samples and a plasma Pan02 sample. A2M is present in one of the PanIn CM samples with a huge Mascot score while in the other sample is not present. Finally, one of the Pan02 CM samples shows a non-significant (NS) A2M Mascot score while in the other there is no A2M present and the Pan02 plasma sample shows a massive Mascot Score.

Once again these results suggest that A2M might be involved not only in defining which normal tissues will develop to cancer but also in determining which cancers will progress further.(10)

Colorectal Cancer

We analyze the possibility that A2M (alpha-2-macroglobulin) can play a role in CRC (colorectal cancer) initiation and/or progression. Here, we analyze by proteomics the presence of A2M in the conditioned culture media of different CRC cell lines either overexpressing P53 or knockout for P53 or treated with vitamin D and from different stages of tumor progression and benign tissues (table 5).

We found out that A2M mascot score in primary tumor cells lines compared with control is either similar or very reduced, being slightly reduced in cell lines treated with vitamin D and /or overexpressing P53. Finally, A2M mascot score is moderately reduced in the metastatic cell line, SW620.

Vitamin D3 has been estimated to lower the incidence of colorectal cancer by 50%, which is consistent with the inverse correlation between dietary vitamin D3 intake or sunlight exposure and human colorectal cancer. Both A2M and Vitamin D play a role in the immune and inflammatory response. A2M acts as a protease inhibitor and cytokine binder, while vitamin D modulates the activity of immune cells. This suggests that A2M may have a role in inhibiting CRC initiation and progression (11).

Lung cancer

We study the possibility that A2M can play a role in lung cancer initiation and/or progression.

Here we analyse by proteomic analysis, the presence of A2M (P010230) in the precipitates derived from CM of different lung cancer cell lines and lung cancer-derived bone metastases (mets) (table 6). We find out that control cell WI38 presents quite a big Mascot score (993), while primary lung cancer cell lines present an average Mascot score level (315-415) and those derived from lymph node (LN) metastases present a slightly higher Mascot score range (330-455). Finally, the bone metastases sample presents a huge Mascot score (1766). This suggests that A2M may have a role in inhibiting lung cancer initiation and progression (12).

Prostate cancer

Here we analyse by proteomic analysis, the presence of A2M (P010230) in the precipitates derived from CM of different prostate cancer cell lines (table 7). We find out that lymph node (LN) derived cell line LNCap presents the highest Mascot score, 724.15, followed by Vcap (cell line derived from vertebral metastases), 449.53. Both these cells lines present androgen sensitivity and are positive for androgen receptor (AR).Moreover, cell lines PC3 (derived from vertebral metastases) and DU145 (derived from brain metastases) and both not sensitive to androgen and negative to AR, present smaller scores (table 7). This might suggest A2M plays a role in prostate cancer progression (13).

Gastric Cancer

We analyzed by proteomics the secretion of A2M by different gastric cancer cell lines derived from primary tumor tissues or lymph node metastases or stage IV tumors in cell culture. We found out that (table 8), A2M presents significant scores in primary gastric cancer cell lines and in lymph node metastases cell lines, whereas is not present or is present in a non-significant way in gastric cancer stage IV cell lines. This points out a role for A2M in gastric cancer initial stages and progression but not in later stages (14).

Bone cancer

Here, we analyzed by proteomics analysis, the content of the precipitates derived from the ultracentrifugation of CM derived from the cell culture of different bone cancer cell lines (table 9). We found out that A2M is present in all cancer cell lines types with significant scores and that is present in higher levels in the osteosarcoma cell line 143B rather than in Ewing’s sarcoma cell line SKES1 what suggests that A2M has a more relevant role is osteosarcoma progression rather that in Ewing’s sarcoma progression (15).

Acute Leukaemia (AML)

Here, we analyze by proteomic analysis the precipitates after ultra-centrifugation of the CM resulting from the cell culture of OCI-AML3 and Kasumi1 cell lines. We compare these proteomic profiles with those derived from the precipitates after ultra-centrifugation of plasma samples of control adult males (Control plasma male 1 and Control plasma male 2) OCI-AML3 cell line is derived from a 57 year-old male with Adult acute myeloid leukemia. Kasumi1 cell line is derived from the peripheral blood of a male AML patient, 7 weeks old.

We found out that (table 11) Mascot scores are high in the Kasumi1 and OCI-AML3 samples and extremely high both in the control plasma male 1 and control plasma male 2 suggesting that A2M may play a role in preventing the development of AML (16).

Conclusions

In most of the cancer types described here, A2M seems to play a role in cancer development and progression, possibly acting as a tumor supressor.

References

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2. Armstrong PB, Quigley JP (1999). "Alpha2-macroglobulin: an evolutionarily conserved arm of the innate immune system". Developmental and Comparative Immunology. 23 (4–5): 375–390.

3. Van Leuven F, Cassiman JJ, Van den Berghe H (December 1986). "Human pregnancy zone protein and alpha 2-macroglobulin. High-affinity binding of complexes to the same receptor on fibroblasts and characterization by monoclonal antibodies". Journal of Biological Chemistry. 261 (35): 16622–16625.

4. Kontomanolis et al (2020). Role of Oncogenes and Tumor-suppressor Genes in Carcinogenesis: A Review.Anticancer Research November 2020, 40 (11) 6009-6015; DOI: https://doi.org/10.21873/anticanres.14622

5. Yang et al. (2020). The role of tumor-associated macrophages (TAMs) in tumor progression and relevant advance in targeted therapy.Acta Pharm Sin B. 2020 Apr 19;10(11):2156–2170.

6. Xing et al, 2016. Roles of low-density lipoprotein receptor-related protein 1 in tumors.Chin J Cancer. 2016 Jan 6;35:6.

7. Lee et al, 2022. Alpha-2-macroglobulin as a novel diagnostic biomarker for human bladder cancer in urinary extracellular vesicles. Front. Oncol., 13 September 2022 Sec. Genitourinary Oncology Volume 12 - 2022 |

8. https://gwyntwrscience.blogspot.com/2025/07/does-alpha-2-macroglobulin-2m-predicts.html

9.https://gwyntwrscience.blogspot.com/2025/08/does-a2m-predicts-cancer-appearance-or.html

10. https://gwyntwrscience.blogspot.com/2025/08/a2m-function-in-pancreatic-cancer-in.html

11.https://gwyntwrscience.blogspot.com/2025/10/a2m-in-colorectal-cancer-issn-2753-8176.html

12.https://gwyntwrscience.blogspot.com/2025/11/a2m-in-lung-cancer-short-report-issn.html

13.https://gwyntwrscience.blogspot.com/2025/12/a2m-in-prostate-cancer-short-report.html

14.https://gwyntwrscience.blogspot.com/2026/03/a2m-in-gastric-cancer-issn-2753-8176.html

15.https://gwyntwrscience.blogspot.com/2026/04/a2m-in-bone-cancer-issn-2753-8176.html

16.https://gwyntwrscience.blogspot.com/2026/05/a2m-in-acute-leukemia-brief-report-issn.html