Gastric cancer (GC) is one of the most common gastrointestinal malignancies, ranking fifth in incidence and third in lethality globally[1]. 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%[2]. 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[3]. Angiogenesis is one of the most fundamental factors that promote the growth and metastasis of CG cells by providing nutrients and oxygen[4]. 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[5]. 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.[6]. 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[7]. 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[8]. 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[10]. 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[15]. 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[16]. 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.