Abstract
Cancer is the leading cause of death worldwide. The World Health Organization (WHO) estimates that 10 million fatalities occurred in 2023. Breast cancer (BC) ranked first among malignancies with 2.26 million cases, lung cancer (LC) second with 2.21 million cases, and colon and rectum cancers (CC, CRC) third with 1.93 million cases. These results highlight the importance of investigating novel cancer prognoses and anti-cancer markers. In this study, we investigated the potential effects of alpha-2 macroglobulin and its receptor, LRP1, on the outcomes of breast, lung, and colorectal malignancies. Immunohistochemical staining was used to analyze the expression patterns of A2M and LRP1 in 545 cases of invasive ductal breast carcinoma (IDC) and 51 cases of mastopathies/fibrocystic breast disease (FBD); 256 cases of non-small cell lung carcinomas (NSCLCs) and 45 cases of non-malignant lung tissue (NMLT); and 108 cases of CRC and 25 cases of non-malignant colorectal tissue (NMCT). A2M and LRP1 expression levels were also investigated in breast (MCF-7, BT-474, SK-BR-3, T47D, MDA-MB-231, and MDA-MB-231/BO2), lung (NCI-H1703, NCI-H522, and A549), and colon (LS 180, Caco-2, HT-29, and LoVo) cancer cell lines. Based on our findings, A2M and LRP1 exhibited various expression patterns in the examined malignancies, which were related to one another. Additionally, the stroma of lung and colorectal cancer has increased levels of A2M/LRP1 areas, which explains the significance of the stroma in the development and maintenance of tumor homeostasis. A2M expression was shown to be downregulated in all types of malignancies under study and was positively linked with an increase in cell line aggressiveness. Although more invasive cells had higher levels of A2M expression, an IHC analysis showed the opposite results. This might be because exogenous alpha-2-macroglobulin is present, which has an inhibitory effect on several cancerous enzymes and receptor-dependent signaling pathways. Additionally, siRNA-induced suppression of the transcripts for A2M and LRPP1 revealed their connection, which provides fresh information on the function of the LRP1 receptor in A2M recurrence in cancer. Further studies on different forms of cancer may corroborate the fact that both A2M and LRP1 have high potential as innovative therapeutic agents.