LAMA1 Promotes Tumor-Associated Macrophages Polarization Towards the M2 Phenotype and Induces Colorectal Cancer

Tumor-associated macrophages (TAMs) differentiate into two main types based on signals from their microenvironment: the classically activated M1 type and the alternatively activated M2 type. An increased presence of M2-type TAMs has been identified in colorectal Cancer patients, and the laminin alpha-1 chain (LAMA1), a key structural component of the extracellular matrix, plays a pivotal role in tumor metastasis. However, the exact mechanism by which LAMA1 promotes the polarization of TAMs towards the M2 phenotype and induces colorectal Cancer remains elusive. In this work, we investigated the levels of LAMA1 and M2 TAMs in peripheral serum and tissue specimens from patients with colorectal Cancer by utilizing Western Blotting, ELISA, and multicolor immunofluorescence. Peripheral blood samples from 20 patients were collected for ELISA analysis, with samples from 5 healthy individuals serving as controls. Additionally, tissue samples from 5 tumor patients and 5 normal controls were used to assess LAMA1 protein levels. Furthermore, statistical methods were employed to analyze the relationship between LAMA1 levels, M2 TAMs infiltration, and the pathological characteristics of colorectal Cancer. Then we utilized Western Blotting, qPCR, and immunofluorescence to detect M2 TAMs markers and polarization mechanism after treatment with exogenous LAMA1 protein. Moreover, we established a mouse subcutaneous tumor model and utilized Western Blotting, immunohistochemistry and multicolor immunofluorescence to assess LAMA1 levels, tumor proliferation and proportion of M2 TAMs. Our analysis revealed that LAMA1 is overexpressed in the tumor microenvironment (TME) of colorectal Cancer patients, which correlates with increased infiltration of M2-type TAMs. Furthermore, we found that the EGFR/Akt/CREB signaling pathway contributes to the polarization of TAMs toward the M2 subtype. Both in vitro and in vivo experiments demonstrated that LAMA1 promotes M2 macrophage polarization and facilitates tumor growth. Overall, these findings highlight a central role for LAMA1 in regulating macrophage polarization through the EGFR/Akt/CREB signaling pathway. Consequently, this process contributes to immune suppression and promotes tumor progression.

Colorectal cancer; Laminin alpha1 chain; M2-Macrophages; Tumor-associated macrophages.