Integrative In Silico and FFPE Tissue Analyses Elucidate Upregulated Genes in Colorectal Cancer Enriched for...

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Tumor-associated monocytes/macrophages, specifically Tie2-expressing monocytes/macrophages (TEMs), are implicated in colorectal cancer (CRC) progression, angiogenesis, and metastasis.
• The precise molecular mechanisms linking TEM infiltration to CRC metastasis and tumor advancement are not fully understood.

Purpose of the Study:

• To investigate the distribution of TEMs within CRC tissues.
• To explore the association between TEMs and gene expression profiles, microvessel density (MVD), and clinical outcomes in CRC patients.

Main Methods:

• Immunohistochemistry was performed on 30 formalin-fixed paraffin-embedded (FFPE) primary CRC samples to identify TEMs (Tie2+/CD14+).
• Gene set enrichment analysis (GSEA) was conducted on in silico transcriptomic datasets of metastatic CRC (mCRC).
• Quantitative reverse transcription PCR (qRT-PCR) validated gene expression in FFPE CRC samples, and Kaplan-Meier analysis assessed survival in 1336 CRC patients.

Main Results:

• TEMs were preferentially located in perivascular regions of CRC and correlated with higher histological grade, tumor size, lymph node metastasis, and increased MVD.
• GSEA revealed enrichment of cell-cell recognition, calcium signaling, transcription regulation, and metalloexopeptidase activity pathways in TEM-rich tumors.
• Upregulation of CCR7, PDGFRA, CITED2, and CPE was confirmed in TEM+ regions; Angiopoietin1 (Ang1) was elevated in TEM+ tumors.
• High expression of CITED2, CPE, and Angiopoietin2 (Ang2) was significantly associated with reduced overall survival in CRC patients.

Conclusions:

• TEM infiltration in CRC is linked to specific transcriptional, biological, and enzymatic pathways that may drive tumor progression and poorer prognosis.
• Candidate biomarkers including CCR7, PDGFRA, CITED2, CPE, and Ang1 warrant further investigation for their role in CRC pathogenesis and potential therapeutic targeting.