Abstract
Annexin A1 is a multi functional molecule which is involved in inflammation, innate and adaptive immune systems, tumor progression and metastasis. We have previously showed the impaired tumor growth, metastasis, angiogenesis and wound healing in annexin A1 knockout mice. While tumor is a piece of heterogeneous mass including not only malignant tumor cells but also the stroma, the importance of the tumor stroma for tumor progression and metastasis is becoming increasingly clear. The tumor stroma is comprised by various components including extracellular matrix and non-malignant cells in the tumor, such as endothelial cells, fibroblasts, immune cells, inflammatory cells. Based on our previous finding of pro-angiogenic functions for annexin A1 in vascular endothelial cell sprouting, wound healing, tumor growth and metastasis, and the previously known properties for annexin A1 in immune cells and inflammation, this study hypothesized that annexin A1 is a key functional player in tumor development, linking the various components in tumor stroma by its actions in endothelial cells and immune cells. Using systems analysis programs commercially available, this paper further compared the gene expression between tumors from annexin A1 wild type mice and annexin A1 knockout mice and found a list of genes that significantly changed in the tumor stroma that lacked annexin A1. This revealed annexin A1 to be an effective regulator in tumor stroma and suggested a mechanism that annexin A1 affects tumor development and metastasis through interaction with the various components in the microenvironment surrounding the tumor cells.
Highlights
We recently showed the pro-angiogenic functions in tumor development for annexin A1 [1] which was previously known as an inflammatory protein
The interaction of annexin A1 with these proteins was previously unknown. We found this list of genes (Table 1) that significantly changed in the tumor stroma that lacked annexin A1
Literature has showed that these genes are associated with tumor and/or tumor stroma: IGH-6 with thymic lymphoma and lymphoblastic leukemia [7,8], TGFBI with neuroblastoma, lung carcinoma, ovarian and prostate cancers, renal, gastrointestinal and brain tumors, colon cancer [9,10,11,12,13,14], PTPRC with human breast tumor stroma [15], MMP13 with skin tumor stroma [16], CCK with human pancreatic cancer [17], TFRC with colon cancer, human esophageal squamous cell carcinoma, human brain tumors, mouse mammary adenocarcinoma and rodent liver tumor [18,19,20,21,22], TIMP2 with human colorectal cancer, human pancreatic carcinoma, human renal cell carcinoma and human squamous cervical carcinoma [23,24,25,26], BRCA1 with human breast tumor stroma [27]
Summary
We recently showed the pro-angiogenic functions in tumor development for annexin A1 [1] which was previously known as an inflammatory protein. Tumor growth and metastasis were significantly decreased when tumors grew in host animals unable to express annexin A1 [1]. Based on our recent finding of proangiogenic functions for annexin A1 in vascular endothelial cell sprouting, wound healing, and tumor growth and metastasis [1], and the previously known properties for annexin A1 in immune cells and inflammation [4], this study hypothesized that annexin A1 is a key functional player in tumor development, linking the various components in tumor stroma by its actions in endothelial cells and immune cells. Of particular importance our systems based approaches provided thorough analysis and generated interesting and thought-provoking results
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