Gastric cancer (GC) is one of the most common gastrointestinal malignancies, ranking fifth in incidence and third in lethality globally. With advances in technology such as endoscopy, more and more patients with GC are being diagnosed and treated in a timely manner, but the overall 5-year survival rate is still less than 40%. Most GC patients are already in the middle or late stages when they are diagnosed, with a median overall survival (OS) less than 12 months. Angiogenesis is one of the most fundamental factors that promote the growth and metastasis of CG cells by providing nutrients and oxygen. When the tumor has advanced metastasis or cannot be excised, the current treatment is based on palliative chemotherapy, when anti-angiogenic therapy can be used as an effective adjuvant treatment. The commonly used anti-angiogenic drugs include bevacizumab, which targets vascular endothelial growth factor-A (VEGF-A), ramucirumab, which targets VEGFR2, and ziv-aflibercept, which targets VEGF-A isoforms, placental growth factor (PLGF), and VEGF-B etc.. However, tumors can develop resistance to anti-angiogenic drugs through a variety of mechanisms, including upregulation of alternative pro-angiogenic signaling pathways, resistance of tumor stromal cells to anti-angiogenic drugs, adaptation of tumor cells to hypoxic environments and alternative mechanisms of tumor vascularization. Therefore, it is of great significance to find new anti-angiogenic targets.
Tumor-associated macrophages (TAM) are the most common tumor-infiltrating immune cells in the tumor microenvironment (TME), accounting for more than 50% of immune cells in the TME and promoting tumorigenesis through various mechanisms such as stimulating angiogenesis, increasing tumor cell invasion and migration, and inhibiting anti-tumor immunity[8, 9]. Macrophages are stimulated by different chemokines released by tumors and stromal cells to differentiate into two phenotypes with dramatic differences: M1 macrophages with antitumor effects and M2 macrophages with pro-tumor effects. M2 macrophages, which occupy the majority of TAM, can produce a variety of pro-angiogenic factors such as VEGF-A and tumor necrosis factor α (TNFα) in hypoxic areas to maintain tumor growth. TAM infiltration in multiple tumors is positively correlated with angiogenesis[11, 12]. And it has been shown that the emergence of anti-VEGF therapy resistance is associated with the aggregation of TAMs in TME[13, 14].
YKL-39, also known as CHI3L2, belongs to the family of chitinase-like proteins (CLPs) that function as both cytokines and growth factors. The CLPs in the human body include YKL-40, YKL-39 and SI-CLP. YKL-39 was originally found in human synoviocytes and chondrocytes and plays a role in regulating autoimmunity and participating in tissue remodeling. It has been shown that YKL-39 expression is elevated in degenerative pathologies and diseases characterized by tissue remodeling, such as osteoarthritis, multiple sclerosis, Alzheimer's disease and amyotrophic lateral sclerosis[17–19]. Recent studies have reported that YKL-39 has monocyte chemotactic and pro-angiogenic activity and is expressed in M2 macrophages from breast, glioma and kidney cancers, affecting tumor angiogenesis, and overexpressed YKL-39 is also associated with poor prognosis[20–22]. However, there are no reports on the relationship between YKL-39 expression and GC biological behavior and prognosis of GC patients.
In this study, we used immunohistochemistry (IHC) and immunofluorescence (IF) to detect the expression of YKL-39, CD68 and CD34 in GC tissues to verify the relationship between YKL-39 expression and macrophage infiltration and its effect on angiogenesis. Our findings support that YKL-39 is expressed in both M2 macrophages and tumor cells with stimulated angiogenesis that correlates with poor prognosis in GC. In summary, our results confirm that YKL-39 has the potential to become a target for anti-TAMs aggregation and anti-tumor angiogenesis in GC.