Genomic profiles of renal cell carcinoma in a small Chinese cohort.

Objectives: Our aim was to describe the molecular characteristics of Renal Cell Carcinoma (RCC) and develop a small panel of RCC-associated genes from a large panel of cancer-related genes. Materials and methods: Clinical data of 55 patients with RCC diagnosed in four hospitals from September 2021 to August 2022 were collected. Among the 55 patients, 38 were diagnosed with clear cell RCC (ccRCC), and the other 17 were diagnosed with non-clear cell RCC (nccRCC), including 10 cases of papillary renal cell carcinoma, 2 cases of hereditary leiomyomatosis and RCC syndrome (HLRCC), 1 eosinophilic papillary RCC, 1 tubular cystic carcinoma, 1 TFE3 gene fusion RCC, and 2 RCC with sarcomatoid differentiation. For each patient, 1123 cancer-related genes and 79 RCC-associated genes were analyzed. Results: The most frequent mutations in a large panel of 1123 cancer-related genes in the overall population of RCC patients were VHL (51%), PBRM1 (35%), BAP1 (16%), KMT2D (15%), PTPRD (15%), and SETD2 (15%). For ccRCC patients, mutations in VHL, PBRM1, BAP1, and SERD2 can reach 74%, 50%, 24%, and 18%, respectively, while for nccRCC patients, the most frequent mutation was FH (29%), MLH3 (24%), ARID1A (18%), KMT2D (18%), and CREBBP (18%). The germline mutation rate in all 55 patients reached 12.7% (five with FH, one with ATM, and one with RAD50). The small panel containing only 79 RCC-associated genes demonstrated that mutations of VHL, PBRM1, BAP1, and SETD2 in ccRCC patients were 74%, 50%, 24%, and 18% respectively, while for the nccRCC cohort, the most frequent mutations were FH (29%), ARID1A (18%), ATM (12%), MSH6 (12%), BRAF (12%), and KRAS (12%). For ccRCC patients, the spectrum of mutations by large and small panels was almost the same, while for nccRCC patients, the mutation spectrum showed some differences. Even though the most frequent mutations (FH and ARID1A) in nccRCC were both demonstrated by large panels and small panels, other less frequent mutations such as MLH3, KMT2D, and CREBBP were not shown by the small panel. Conclusion: Our study revealed that nccRCC is more heterogeneous than ccRCC. For nccRCC patients, the small panel shows a more clear profile of genetic characteristics by replacing MLH3, KMT2D, and CREBBP with ATM, MSH6, BRAF, and KRAS, which may help predict prognosis and make clinical decisions.

Fabrication and application of a wireless high-definition endoscopic system in urological surgeries.

OBJECTIVE: To introduce a wireless high-definition endoscopic system (WHES) and compare it with a Storz high-definition (HD) system for image resolution, colour resolution, weight, and costs. MATERIALS AND METHODS: The WHES incorporated a portable light-emitting diode light source and a wireless camera module, which can be compatible with different types of endoscopes. Images were wirelessly transmitted to a monitor or mobile platform such as smartphone through a receiver. The International Standards Organization 12233 resolution chart image was used for the comparison of image resolution and Munsell Colour Checker Chart for colour resolution. In all, 38 endourologists used a Likert questionnaire to blindly evaluate cystoscopic images from a patient with haematuria. The surgical team was asked about the overall performance of the WHES in 20 laparoscopic adrenalectomies using a unvalidated subjective survey. RESULTS: There was no difference in image resolution between the two systems (5.82 vs 5.89 line pairs/mm). Without lens and respective light sources, there were better purple (ΔE = 21.48 vs 28.73), blue (ΔE = 34.88 vs 38.6) and red colour resolution (ΔE = 29.01 vs 35.45) for the WHES camera (P < 0.05), but orange (ΔE = 43.45 vs 36.52) and yellow (ΔE = 52.7 vs 35.93) resolutions were better for the Storz HD camera (P < 0.05). Comparing the WHES to a Storz laparoscopic system, the Storz system still had better resolution of orange and yellow, while the resolution of purple, blue, and red was similar for the two systems. The expert comments on resolution, brightness, and colour for cystoscopy were not statistically different, but the ergonomics score for the WHES was higher (3.7 vs 3.33, P = 0.038). The overall cost of the WHES was $23 000-25 000 compared with $45 000-50 000 for a Storz system. There were 100% general satisfaction for the WHES in the survey. CONCLUSION: We developed a new WHES that provides the same resolution images as a Storz laparoscopic system and acceptable colour resolution with the advantages of wireless connection, small volume, low cost, portability, and high-speed wireless transmission.

hsa_circ_0062019 promotes the proliferation, migration, and invasion of prostate cancer cells via the miR-195-5p/HMGA2 axis.

Circular RNA (circRNA) is a new class of non-coding RNA. It was reported that circRNA involves in the metastasis of cancer. The aim of this study is to explore the role and mechanism of circRNA hsa_circ_0062019 in the development of prostate cancer (PCa). Our results showed that hsa_circ_0062019 was highly expressed in PCa cell lines. Cell Counting Kit-8 assay revealed that upregulation of hsa_circ_0062019 boosted PCa cell proliferation, and silencing of hsa_circ_0062019 inhibited cell proliferation. Meanwhile, transwell assay proved that upregulation of hsa_circ_0062019 facilitated PCa cell invasion and migration, while downregulation of hsa_circ_0062019 inhibited these malignant phenotypes. Furthermore, luciferase reporter assay proved the binding of hsa_circ_0062019 with miR-195-5p and the binding between miR-195-5p and high mobility group AT-hook 2 (HMGA2), suggesting that hsa_circ_0062019 promoted the expression of HMGA2 by sponging miR-195-5p. In addition, our results revealed that the hsa_circ_0062019-induced PCa cell malignant phenotypes were notably reversed by the downregulation of HMGA2. Overall, our study demonstrated that hsa_circ_0062019 promoted PCa cell proliferation, migration, and invasion via upregulation of HMGA2 expression by sponging miR-195-5p. Our study proved a novel molecular mechanism of PCa development and provided a potential target for the treatment of PCa.

The risk factors related to the severity of pain in patients with Chronic Prostatitis/Chronic Pelvic Pain Syndrome.

BACKGROUND: Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is a disease with diverse clinical manifestations, such as pelvic pain or perineal pain. Although recent studies found several risk factors related to the pain severity of CP/CPPS patients, results were inconsistent. Here, we aimed to identify novel risk factors that are closely related to the severity of pain in patients with CP/CPPS. METHODS: We retrospectively collected the clinical records from patients with CP/CPPS from March 2019 to October 2019. The questionnaire was used to obtain related parameters, such as demographics, lifestyle, medical history, etc. To identify potential risk factors related to pain severity, we used the methods of univariate and multivariate logistic regression analyses. Further, to confirm the relationship between these confirmed risk factors and CP/CPPS, we randomly divided CP/CPPS patients into the training and the validation cohorts with a ratio of 7:3. According to the co-efficient result of each risk factor calculated by multivariate logistic regression analysis, a predicting model of pain severity was established. The receiver operating characteristic curve (ROC), discrimination plot, calibration plot, and decision curve analyses (DCA) were used to evaluate the clinical usage of the current model in both the training and validation cohorts. RESULTS: A total of 272 eligible patients were enrolled. The univariate and multivariate logistic regression analysis found that age [odds ratio (OR): 2.828, 95% confidence intervals (CI): 1.239-6.648, P = 0.004], holding back urine (OR: 2.413, 95% CI: 1.213-4.915, P = 0.005), anxiety or irritability (OR: 3.511, 95% CI: 2.034-6.186, P < 0.001), contraception (OR: 2.136, 95% CI:1.161-3.014, P = 0.029), and smoking status (OR: 1.453, 95% CI: 1.313-5.127, P = 0.013) were the risk factors of pain severity. We then established a nomogram model, to test whether these factors could be used to predict the pain severity of CP/CPPS patients in turn. Finally, ROC, DCA, and calibration analyses proved the significance and stability of this nomogram, further confirmed that these factors were closely related to the pain severity of CP/CPPS patients. CONCLUSIONS: We identify age, holding back urine, anxiety or irritability, contraception, and smoking are risk factors closely related to the pain severity in patients with CP/CPPS. Our results provide novel inspirations for clinicians to design the personalized treatment plan for individual CP/CPPS patient who has suffered different encounters.

Single-cell multi-omics analysis presents the landscape of peripheral blood T-cell subsets in human chronic prostatitis/chronic pelvic pain syndrome.

Cumulative evidence suggests that abnormal differentiation of T lymphocytes influences the pathogenesis of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Thus, understanding the immune activation landscape of CP/CPPS would be helpful for improving therapeutic strategies. Here, we utilized BD™ AbSeq to digitally quantify both the protein and mRNA expression levels in single peripheral blood T cells from two CP/CPPS patients and two healthy controls. We utilized an integrated strategy based on canonical correlation analysis of 10 000+ AbSeq profiles and identified fifteen unique T-cell subpopulations. Notably, we found that the proportion of cluster 0 in the CP/CPPS group (30.35%) was significantly increased compared with the proportion in the healthy control group (9.38%); cluster 0 was defined as effector T cells based on differentially expressed genes/proteins. Flow cytometry assays confirmed that the proportions of effector T-cell subpopulations, particularly central memory T cells, T helper (Th)1, Th17 and Th22 cells, in the peripheral blood mononuclear cell populations of patients with CP/CPPS were significantly increased compared with those of healthy controls (P < 0.05), further confirming that aberration of effector T cells possibly leads to or intensifies CP/CPPS. Our results provide novel insights into the underlying mechanisms of CP/CPPS, which will be beneficial for its treatment.

Accumulation of stabilin-1 positive macrophages in the early stage of gastric cancer is associated with short cumulative survival.

The scavenger receptor stabilin-1 has been reported to be expressed by tumor-associated macrophages (TAMs) and to facilitate tumor growth and metastasis in mouse models of breast carcinoma and melanoma. However, to the best of our knowledge, its expression and association with prognosis in human gastric cancer has not been evaluated. The present study investigated the expression of stabilin-1 and its association with clinicopathological parameters in patients with gastric cancer. The expression of stabilin-1 was evaluated by immunohistochemical staining of gastric cancer tissue samples of 371 Chinese patients with primary gastric adenocarcinoma. Confocal laser scanning microscopy was used to determine the cellular source of stabilin-1 in the gastric cancer tissues using anti-CD68, anti-CD163, anti-stabilin-1 and anti-secreted protein acidic and rich in cysteine antibodies. A higher number of stabilin-1-positive cells were observed in the cancer tissues of primary gastric adenocarcinoma compared with adjacent non-cancerous tissues of primary gastric adenocarcinoma (P<0.001); the majority of stabilin-1-positve cells were CD68+/CD163+ macrophages. Poorly-differentiated gastric cancer tissue had fewer stabilin-1-positive cells compared with medium- and well-differentiated gastric cancer (P=0.030). A higher number of stabilin-1-positive cells were found in the early Tumor-Node-Metastasis (TNM) stage (TNM I stage) of primary gastric adenocarcinoma (P=0.038) compared with TNM stage IV. For patients with TNM stage I disease, a higher number of stabilin-1-positive TAMs was associated with shorter cumulative survival (P<0.05). Overall, stabilin-1 was found to be expressed by CD68+ TAMs in human gastric cancer. The high expression of stabilin-1 in TNM stage I disease was associated with poor patient survival, indicating the clinical significance of stabilin-1 in gastric cancer.

Clinical value of prostate-specific antigen combined with tumor abnormal protein (TAP) in the diagnosis of prostate puncture.

BACKGROUND: In this study, we aimed to test the clinical value of total prostate-specific antigen (T-PSA), free prostate-specific antigen (F-PSA), and T-PSA combined with tumor abnormal glycoprotein (TAP) for early diagnosis of prostate cancer. METHODS: The levels of serum T-PSA and F-PSA were measured in 105 malignant prostate tumors and 97 benign prostate tissues using chemiluminescence immunoassay. The concentration of TAP in the serum of patients was tested by the agglutination method. Differences in PSA levels and F-PSA/T-PSA ratio in two patient groups were analyzed by t-test. TAP concentrations were compared using Chi-square test. The sensitivity, specificity, and accuracy of PSA combined with TAP for the diagnosis of prostate cancer were analyzed. RESULTS: The serum PSA level in patients with malignant tumors were higher than that in patients with benign tumors (P<0.0001). TAP positivity in patients with prostate cancer was higher than that in patients with benign tumors (P<0.0001). The number of cases with positive and weakly positive TAP values in three intervals of T-PSA concentrations was higher in patients with malignant tumors, while the number of negative cases was higher in patients with benign tumors (P<0.05). The sensitivity, specificity, and accuracy of T-PSA combined with TAP in the diagnosis of prostate cancer were 97.14%, 67.01%, and 81.68% respectively, which was higher compared to the other measured markers. CONCLUSIONS: The results of our study indicate that PSA combined with TAP is a sensitive, specific, and accurate diagnostic marker of prostate cancer. Therefore, it has potential clinical relevance for the early screening of prostate cancer.

Expression of Narcissus pseudonarcissus lectin and mannose receptor positive macrophages predict progression and prognosis of patients with gastric cancer.

BACKGROUND: Mannose receptor (MR) is an immune adhesion molecule and is mainly expressed in macrophages and nonmature dendritic cells. The ligand mannose, one of the natural ligands of MR, is a monosaccharide, which is localized in the envelope or cytoplasm of macrophages. The aim of this study was to investigate expression of MR and its ligand mannose in tumor tissues of primary advanced gastric cancer and to evaluate the predictive and prognostic value of the positive cells in gastric cancer patients. METHODS: Histochemical staining for Narcissus pseudonarcissus lectin (NPL) and immunohistochemical envision two-step assay for MR were used to detect expression of NPL and MR in primary advanced gastric adenocarcinoma tissues. Adjacent non-cancerous gastric tissues of the patients were used as controls. Relationship of NPL and MR expression in the tumor tissues with clinicopathological features and survival time of the gastric cancer patients were analyzed. RESULTS: Numbers of NPL+ and MR+ macrophages in stromal tissues of gastric cancer were significantly higher than those in the adjacent non-cancerous gastric tissues (P=0.006; P<0.001). NPL expression in the primary tumor tissues was significantly more dominant than that in the adjacent non-cancerous gastric tissues (P=0.003). Expression of both the molecules in macrophages in tumor tissues was negatively correlated (r=-0.363, P=0.009). TNM stage of the patients was closely correlated to number of MR+ macrophages and NPL expression in the stromal tissues of gastric cancer (P=0.009 and P=0.020). Kaplan-Meier survival model data showed that the patients with low counting of NPL+ macrophages and high counting of MR+ macrophages significantly led to worse disease progression and poorer prognosis (P=0.008). Cox regression analysis further demonstrated that high expression of MR+ macrophages was an independent predictor of poor prognosis in patients with gastric cancer (P=0.033). CONCLUSIONS: Occurrence of mannose and MR in tumor tissues of gastric cancer might be prognostic factors for estimating risk of gastric cancer patients.

SI-CLP inhibits the growth of mouse mammary adenocarcinoma by preventing recruitment of tumor-associated macrophages.

Chitinase-like proteins (CLP) are chitin-binding proteins that lack chitin hydrolyzing activity, but possess cytokine-like and growth factor-like properties, and play crucial role in intercellular crosstalk. Both human and mice express two members of CLP family: YKL-40 and stabilin-1 interacting chitinase-like protein (SI-CLP). Despite numerous reports indicating the role of YKL-40 in the support of angiogenesis, tumor cell proliferation, invasion and metastasis, the role of its structurally related protein SI-CLP in cancer was not reported. Using gain-of-function approach, we demonstrate in the current study that the expression of recombinant SI-CLP in mouse TS/A mammary adenocarcinoma cells results in significant and persistent inhibition of in vivo tumor growth. Using quantitative immunohistochemistry, we show that on the cellular level this phenomenon is associated with reduced infiltration of tumor-associated macrophages (TAMs), CD4+ and FoxP3+ cells in SI-CLP expressing tumors. Gene expression analysis in TAM isolated from SI-CLP-expressing and control tumors demonstrated that SI-CLP does not affect macrophage phenotype. However, SI-CLP significantly inhibited migration of murine bone-marrow derived macrophages and human primary monocytes toward monocyte-recruiting chemokine CCL2 produced in the tumor microenvironment (TME). Mechanistically, SI-CLP did not affect CCL2/CCR2 interaction, but suppressed cytoskeletal rearrangements in response to CCL2. Altogether, our data indicate that SI-CLP functions as a tumor growth inhibitor in mouse breast cancer by altering cellular composition of TME and blocking cytokine-induced TAM recruitment. Taking into consideration weak to absent expression of SI-CLP in human breast cancer, it can be considered as a therapeutic protein to block TAM-mediated support of breast tumor growth.

PPARγ-activation increases intestinal M1 macrophages and mitigates formation of serrated adenomas in mutant KRAS mice.

To identify novel hubs for cancer immunotherapy, we generated C57BL/6J mice with concomitant deletion of the drugable transcription factor PPARγ and transgenic overexpression of the mutant KRASG12V oncogene in enterocytes. Animals developed epithelial hyperplasia, transmural inflammation and serrated adenomas in the small intestine with infiltration of CD3+ FOXP3+ T-cells and macrophages into the lamina propria of the non-malignant mucosa. Within serrated polyps, CD3+ CD8+ T-cells and phosphorylated ERK1/2 were reduced and the senescence marker P21 and macrophage counts up-regulated, indicative of an immunosuppressive tissue microenvironment. Treatment of mutant KRASG12V mice with the PPARγ-agonist rosiglitazone augmented M1 macrophage numbers, reduced IL4 expression and diminished polyp load in mice. Rosiglitazone also promoted M1 polarisation of human THP1-derived macrophages and decreased Il4 mRNA in isolated murine lymphocytes. Thus, inhibition of the oncogenic driver mutant RAS by PPARγ in epithelial and immune cell compartments may be a future target for the prevention or treatment of human malignancies associated with intestinal inflammation.

IL-4 driven transcription factor FoxQ1 is expressed by monocytes in atopic dermatitis and stimulates monocyte migration.

Monocytes are actively recruited at sites of chronic inflammation. However, molecular factors involved in this process are not fully elucidated. Here, we show that cytokine IL-4 which is implicated in the development of chronic inflammatory disease atopic dermatitis (AD) induces expression of transcription factor FoxQ1 in human monocytes and macrophages. FoxQ1 mRNA levels were elevated in monocytes of AD patients compared to healthy donors. Overexpression of FoxQ1 in RAW 264.7 monocytic cells facilitated their migration towards MCP-1 and was associated with decreased expression of migration-regulating genes (claudin 11 and plexin C1). Furthermore, FoxQ1 overexpression in RAW cells accelerated TNFα secretion after LPS challenge. Overall, our results indicate that FoxQ1 stimulates monocyte motility, increases pro-inflammatory potential, and directs monocyte migration towards MCP-1 that is crucial for monocyte influx into inflammatory sites. This mechanism could contribute to the pathogenesis of chronic inflammatory disorders such as AD.

The relationship between stromal cell derived SPARC in human gastric cancer tissue and its clinicopathologic significance.

BACKGROUND: We aimed to investigate the cellular source of secreted protein acidic and rich in cysteine (SPARC) in gastric cancer tissues and the relationship between SPARC expression and its prognostic significance. METHODS: The expression of SPARC in 365 primary advanced gastric adenocarcinomas and 39 non-cancerous tissues was evaluated by immunohistochemical staining. Double-immunofluorescence staining was used to reveal the cellular source of SPARC in tumor tissues. Western blotting and immunofluorescence staining were applied for verifying the endogenous expression of SPARC in human cell lines of gastric cancer and fibroblast. RESULTS: Higher positivity of SPARC was observed in gastric cancer tissues than non-cancerous gastric tissues (P=0.000). The positivity of SPARC was related to age (P=0.032), tumor location (P=0.018), depth of tumor invasion (P=0.011), nodal metastasis (P=0.023), TNM stage (P=0.034), the differentiation degree (P=0.006) and pathological type (P=0.002) of gastric cancer. SPARC in gastric cancer tissues was mainly expressed by cancer-associated fibroblasts. SPARC also appeared in neovascular endothelial cells and a few tumor-associated macrophages. The endogenous expression of SPARC in fibroblasts was suppressed by mucus-producing gastric adenocarcinoma cells(MKN-45). Increased SPARC expression in gastric cancer tissue was suggestive of a shorter cumulative survival in the patients with gastric adenocarcinoma, though this difference was not statistically significant(P>0.05). CONCLUSION: SPARC in human gastric cancer tissue was derived from the stromal cells and was mainly produced by cancer-associated fibroblasts. Production of SPARC in fibroblasts was reduced by the mucus-producing gastric adenocarcinoma cells.

CD68+, but not stabilin-1+ tumor associated macrophages in gaps of ductal tumor structures negatively correlate with the lymphatic metastasis in human breast cancer.

Tumor associated macrophages (TAM) support tumor growth and metastasis in several animal models of breast cancer, and TAM amount is predictive for efficient tumor growth and metastatic spread via blood circulation. However, limited information is available about intratumoral TAM heterogeneity and functional role of TAM subpopulations in tumor progression. The aim of our study was to examine correlation of TAM presence in various morphological segments of human breast cancer with clinical parameters. Thirty six female patients with nonspecific invasive breast cancer T1-4N0-3M0 were included in the study. Morphological examination was performed using Carl Zeiss Axio Lab.A1 and MiraxMidiZeiss. Immunohistochemical and immunofluorescence/confocal microcopy analysis was used to detect CD68 and stabilin-1 in 5 different tumor segments: (1) areas with soft fibrous stroma; (2) areas with coarse fibrous stroma; (3) areas of maximum stromal-and-parenchymal relationship; (4) parenchymal elements; (5) gaps of ductal tumor structures. The highest expression of CD68 was in areas with soft fibrous stroma or areas of maximum stromal-and-parenchymal relationship (79%). The lowest expression of CD68 was in areas with coarse fiber stroma (23%). Inverse correlation of tumor size and expression of CD68 in gaps of tubular tumor structures was found (R=-0.67; p=0.02). In case of the lymph node metastases the average score of CD68 expression in ductal gaps tumor structures was lower (1.4±0.5) compared to negative lymph nodes case (3.1±1.0; F=10.9; p=0.007). Confocal microscopy identified 3 phenotypes of TAM: CD68+/stabilin-1-; CD68+/stabilin-1+ (over 50%); and CD68-/stabilin-1+. However, expression of stabilin-1 did not correlate with lymph node metastasis. We concluded, that increased amount of CD68+TAM in gaps of ductal tumor structures is protective against metastatic spread in regional lymph nodes.

A combinatorial αß T cell receptor expressed by macrophages in the tumor microenvironment.

Recent evidence indicates the presence of macrophage subpopulations that express the TCRαß in two major inflammatory diseases, tuberculosis and atherosclerosis. Inflammation is also a well-established attribute of cancer progression and macrophages are one of the major immune cells that infiltrate tumors. Here, we demonstrate that the macrophage-TCRαß is expressed in the tumor microenvironment of human and murine malignancies. We identify TCRαß+ macrophages in each case of four randomly selected distinct human tumor entities. In human tumor tissues, the TCRαß expressed by macrophages in the tumor microenvironment is a combinatorial and individual-specific immune receptor. Furthermore, we routinely find TCRαß+ macrophage subpopulations in experimental tumors (TS/A, mammary adenocarcinoma) which we induced both in normal mice and mice deficient in the macrophage receptor stabilin-1. Expression of the combinatorial murine tumor macrophage TCRαß is individual-specific and independent of stabilin-1. These results demonstrate that TCRαß expression is a characteristic feature of macrophages in the tumor microenvironment and identify an as yet unrecognized flexible element in the macrophage-based host response to tumors.

Stabilin-1 is expressed in human breast cancer and supports tumor growth in mammary adenocarcinoma mouse model.

Stabilin-1 is a multifunctional scavenger receptor expressed on alternatively-activated macrophages. Stabilin-1 mediates phagocytosis of "unwanted-self" components, intracellular sorting, and endocytic clearance of extracellular ligands including SPARC that modulates breast cancer growth. The expression of stabilin-1 was found on tumor-associated macrophages (TAM) in mouse and human cancers including melanoma, lymphoma, glioblastoma, and pancreatic insulinoma. Despite its tumor-promoting role in mouse models of melanoma and lymphoma the expression and functional role of stabilin-1 in breast cancer was unknown. Here, we demonstrate that stabilin-1 is expressed on TAM in human breast cancer, and its expression is most pronounced on stage I disease. Using stabilin-1 knockout (ko) mice we show that stabilin-1 facilitates growth of mouse TS/A mammary adenocarcinoma. Endocytosis assay on stabilin-1 ko TAM demonstrated impaired clearance of stabilin-1 ligands including SPARC that was capable of inducing cell death in TS/A cells. Affymetrix microarray analysis on purified TAM and reporter assays in stabilin-1 expressing cell lines demonstrated no influence of stabilin-1 expression on intracellular signalling. Our results suggest stabilin-1 mediated silent clearance of extracellular tumor growth-inhibiting factors (e.g. SPARC) as a mechanism of stabilin-1 induced tumor growth. Silent clearance function of stabilin-1 makes it an attractive candidate for delivery of immunomodulatory anti-cancer therapeutic drugs to TAM.

Role of chitinase-like proteins in cancer.

Chitinase-like proteins (CLPs) are lectins combining properties of cytokines and growth factors. Human CLPs include YKL-40, YKL-39 and SI-CLP that are secreted by cancer cells, macrophages, neutrophils, synoviocytes, chondrocytes and other cells. The best investigated CLP in cancer is YKL-40. Serum and plasma levels of YKL-40 correlate with poor prognosis in breast, lung, prostate, liver, bladder, colon and other types of cancers. In combination with other circulating factors YKL-40 can be used as a predictive biomarker of cancer outcome. In experimental models YKL-40 supports tumor initiation through binding to RAGE, and is able to induce cancer cell proliferation via ERK1/2-MAPK pathway. YKL-40 supports tumor angiogenesis by interaction with syndecan-1 on endothelial cells and metastatic spread by stimulating production of pro-inflammatory and pro-invasive factors MMP9, CCL2 and CXCL2. CLPs induce production of pro- and anti-inflammatory cytokines and chemokines, and are potential modulators of inflammatory tumor microenvironment. Targeting YKL-40 using neutralizing antibodies exerts anti-cancer effect in preclinical animal models. Multifunctional role of CLPs in regulation of inflammation and intratumoral processes makes them attractive candidates for tumor therapy and immunomodulation. In this review we comprehensively analyze recent data about expression pattern, and involvement of human CLPs in cancer.