Antibody Directed against Human YKL-40 Increases Tumor Volume in a Human Melanoma Xenograft Model in Scid Mice

Salamon, Johannes; Hoffmann, Tatjana; Elies, Eva; Peldschus, Kersten; Johansen, Julia S.; Lüers, Georg H.; Schumacher, Udo; Wicklein, Daniel

doi:10.1371/journal.pone.0095822

Cited by 13 publications

(14 citation statements)

References 31 publications

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“…Riabov et al [ 29 ] assumed that the most important are overlapping mechanisms such as biology of tumor cells, reaction of immune system, as well as dependence between YKL-40 and TAM. Salamon J et al [ 30 ] on the other side presented very interesting results with antibody against YKL-40. The aim of their study was to evaluate the effect of anti-YKL-40 monoclonal antibody on tumor growth and morphology in xenograft model of human melanoma, as well as pancreatic adenocarcinoma in scid mice.…”

Section: Discussionmentioning

confidence: 99%

“…The aim of presented study was to evaluate the clinical utility of serum concentrations of VEGF, MMP-2, MMP-9, TIMP-1, and YKL-40 in patients with melanoma at locoregional stage. Marker selection was based on their role in cancerogenesis and the possibility of the application of targeted therapy [ 30 – 32 ]. We have proved that increased concentrations of TIMP-1 were unfavorable prognostic factors for both disease-free survival and overall survival, as well as for relation between YKL-40 and ulceration.…”

Section: Discussionmentioning

confidence: 99%

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Serum markers in early-stage and locally advanced melanoma

et al. 2015

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The identification of prognostic factors in cutaneous melanoma allows choosing the most effective treatment, especially in group of patients with locoregional disease. Markers related to carcinogenesis and angiogenesis in particular have effect on the course of the disease. The aim of this study was to evaluate clinical utility of vascular endothelial growth factor (VEGF), matrix metalloproteinase 2 (MMP-2), MMP-9, tissue inhibitors of metalloproteinase 1 (TIMP-1), and YKL-40 in serum of melanoma patients at pathological stages I–III. We included 148 adult patients with melanoma. The median follow-up was 40 months. Disease recurrence was observed in 43 patients; 3-year disease-free survival (DFS) rate was 71.7 %; 35 patients died; and the 3-year overall survival (OS) rate was 85 %. Concentrations of VEGF, MMP-2, MMP-9, TIMP-1, and YKL-40 were measured by ELISA kits. VEGF, MMP-9, TIMP-1, and YKL-40 were significantly higher in group of patients than in controls. Increased concentrations of TIMP-1 were related to patient survival, which in the group of lower and increased TIMP-1, disease-free survival amounted to 81 vs. 61 % (p = 0.014) and overall survival −88 vs. 82 % (p = 0.050), respectively. An increased concentration of YKL-40 was observed in 59 % of patients with ulceration and in 26 % of patients without ulceration (p = 0.012). We have found a clinically significant correlation between YKL-40 and MMP-9 (rho = 0.363; p = 0.004) as well as YKL-40 and VEGF (rho = 0.306; p = 0.018). In melanoma patients at stages I–III, the high concentrations of TIMP-1 in serum predicted adverse prognosis. YKL-40 was associated with ulceration of primary tumor, which is a very important prognostic factor.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Serum markers in early-stage and locally advanced melanoma

et al. 2015

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“… 26 The inhibiting effect of anti-YKL-40 antibody (mAY) on tumor growth was demonstrated in mouse model of melanoma and glioblastoma. 27 , 28 …”

Section: Introductionmentioning

confidence: 99%

Tumor-associated macrophages in human breast cancer produce new monocyte attracting and pro-angiogenic factor YKL-39 indicative for increased metastasis after neoadjuvant chemotherapy

et al. 2018

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In breast cancer, the tumor microenvironment plays a critical role in the tumor progression and responses to therapy. Tumor-associated macrophages (TAMs) are major innate immune cells in tumor microenvironment that regulate intratumoral immunity and angiogenesis by secretion of cytokines, growth factors as well as chitinase-like proteins (CLPs), that combine properties of cytokines and growth factors. YKL-39 is a chitinase-like protein found in human and absent in rodents, and its expression in TAMs and role in breast cancer progression was not studied to date. Here for the first time we demonstrate that YKL-39 is expressed on TAMs, predominantly positive for stabilin-1, but not by malignant cells or other stromal cells in human breast cancer. TGF-beta in combination with IL-4, but not IL-4 alone was responsible of the stimulation of the production of YKL-39 in human primary macrophages. Mechanistically, stabilin-1 directly interacted with YKL-39 and acted as sorting receptor for targeting YKL-39 into the secretory pathway. Functionally, purified YKL-39 acted as a strong chemotactic factor for primary human monocytes, and induced angiogenesis in vitro. Elevated levels of YKL-39 expression in tumors after neoadjuvant chemotherapy (NAC) were predictive for increased risk of distant metastasis and for poor response to NAC in patients with nonspecific invasive breast carcinoma. Our findings suggest YKL-39 as a novel therapeutic target, and blocking of its activity can be combined with NAC in order to reduce the risk of metastasis in breast cancer patients.

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“…Application of anti-YKL-40 antibody in the U87 glioblastoma mouse models resulted in the suppression of xenograft tumor growth as well as angiogenesis (97). However, an opposite result was seen in BALB/c-scid mice injected with human melanoma cells; the tumor growth was enhanced after anti-YKL-40 antibody treatment (98). The contradictory results between glioblastoma and melanoma mouse models can be explained by the different mouse strains and antibodies used in the studies.…”

Section: Chitinase-like Proteins In Cancermentioning

confidence: 99%

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

2020

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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.

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Antibody Directed against Human YKL-40 Increases Tumor Volume in a Human Melanoma Xenograft Model in Scid Mice

Cited by 13 publications

References 31 publications

Serum markers in early-stage and locally advanced melanoma

Serum markers in early-stage and locally advanced melanoma

Tumor-associated macrophages in human breast cancer produce new monocyte attracting and pro-angiogenic factor YKL-39 indicative for increased metastasis after neoadjuvant chemotherapy

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

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