YKL-39 as a Potential New Target for Anti-Angiogenic Therapy in Cancer

Abstract

YKL-39 belongs to the evolutionarily conserved family of Glyco_18-containing proteins composed of chitinases and chitinase-like proteins. Chitinase-like proteins (CLPs) are secreted lectins that lack hydrolytic activity due to the amino acid substitutions in their catalytic domain and combine the functions of cytokines and growth factors. One of the major cellular sources that produce CLPs in various pathologies, including cancer, are macrophages. Monocytes recruited to the tumor site and programmed by tumor cells differentiate into tumor-associated macrophages (TAMs), which are the primary source of pro-angiogenic factors. Tumor angiogenesis is a crucial process for supplying rapidly growing tumors with essential nutrients and oxygen. We recently determined that YKL-39 is produced by tumor-associated macrophages in breast cancer. YKL-39 acts as a strong chemotactic factor for monocytes and stimulates angiogenesis. Chemotherapy is a common strategy to reduce tumor size and aggressiveness before surgical intervention, but chemoresistance, resulting in the relapse of tumors, is a common clinical problem that is critical for survival in cancer patients. Accumulating evidence indicates that TAMs are essential regulators of chemoresistance. We have recently found that elevated levels of YKL-39 expression are indicative of the efficiency of the metastatic process in patients who undergo neoadjuvant chemotherapy. We suggest YKL-39 as a new target for anti-angiogenic therapy that can be combined with neoadjuvant chemotherapy to reduce chemoresistance and inhibit metastasis in breast cancer patients.

Keywords: YKL-39; angiogenesis; cancer; chemotactic activity; chitinase-like proteins; neoadjuvant chemotherapy; tumor-associated macrophages.

Figure 1

Structure of mammalian chitinases and chitinase-like proteins. (A) Domain organization of Glyco_18-containing proteins. (B) Critical amino acids in catalytic sites of mammalian Glyco_18-containing proteins (12), Copyright by de Gruyter.

Figure 2

Schematic illustration of YKL-39 activity in cancer. Monocytes are recruited into growing tumors by chemotactic factor YKL-39 secreted by TAMs in the tumor microenvironment, where TAMs support the survival and growth of cancer cells. Monocytes differentiate in the tumor tissue into TAMs, which are key inducers of the angiogenic switch. YKL-39 possesses pro-angiogenic activity and causes stimulation of angiogenesis that can lead to the intensive intravasation of cancer cells to the blood vessels.