Expression and Clinical Significance of Non B Cell-Derived Immunoglobulins in the Urinary System and Male Reproductive System.

The urinary system comprises kidneys, ureters, bladder, and urethra with its primary function being excretion, referring to the physiological process of transporting substances that are harmful or surplus out of the body. The male reproductive system consists of gonads (testis), vas deferens, and accessory glands such as the prostate. According to classical immunology theory, the tissues and organs mentioned above are not thought to produce immunoglobulins (Igs), and any Ig present in the relevant tissues under physiological and pathological conditions is believed to be derived from B cells. For instance, most renal diseases are associated with uncontrolled inflammation caused by pathogenic Ig deposited in the kidney. Generally, these pathological Igs are presumed to be produced by B cells. Recent studies have demonstrated that renal parenchymal cells can produce and secrete Igs, including IgA and IgG. Glomerular mesangial cells can express and secrete IgA, which is associated with cell survival and adhesion. Likewise, human podocytes demonstrate the ability to produce and secrete IgG, which is related to cell survival and adhesion. Furthermore, renal tubular epithelial cells also express IgG, potentially involved in the epithelial-mesenchymal transition (EMT). More significantly, renal cell carcinoma, bladder cancer, and prostate cancer have been revealed to express high levels of IgG, which promotes tumour progression. Given the widespread Ig expression in the urinary and male reproductive systems, continued efforts to elucidate the roles of Igs in renal physiological and pathological processes are necessary.

A case report of giant gangliocytoma of mediastinum.

Background: Gangliocytoma is an uncommon disease. In this report, we report a patient who was admitted to the hospital with a mediastinal tumor which is giant rarely. Case Description: A 30-year-old male patient was found to have a mediastinal mass 2 weeks ago during a routine examination. The patient occasionally had chest pain before 1 month. Computed tomography of the chest showed a mass occupying the posterior mediastinum and located anterior to the spine, above the diaphragm. The mass is removed by thoracoscopic surgery. In the surgical field of view, the tumor was loosely adhered to the surrounding organs and was freed by blunt-sharp combination Histologically confirmed mediastinal gangliocytoma with a size of 9.5 cm × 6.0 cm × 3.0 cm. The surgery was successful, and the patient's symptoms were completely relieved after the surgery. The patient underwent chest X-ray review at the 6th month after discharge, and no recurrence was found. Conclusions: Gangliocytomas are rare tumors of the peripheral nervous system. However, most of these tumors are retroperitoneal and are more common in children and young adults. Ganglioneuromas arise from neural crest cells. Most of these tumors are asymptomatic, but some may develop high blood pressure and flushing. Surgery is the best way to treat such tumors, and attention should be paid to protecting the normal tissue around the tumor during surgery to prevent postoperative complications.

Radiofrequency Ablation Combined with Radioactive Seed Implantation for Nonsmall Cell Lung Cancer.

The aim of this study is to investigate the value of radiofrequency ablation combined with radioactive seed implantation in nonsmall cell lung cancer treatment. 30 patients with primary nonsmall cell lung cancer were randomly divided into two groups. Group A was treated with radiofrequency ablation combined with radiation seed implantation, and group B was treated with radiofrequency ablation only. We compared the incidence of complications in the two groups and reviewed the effective percentage every 3 months. All patients were treated successfully, and there were no deaths during treatment. There were no deaths and no cases of distant organ metastasis in nine months of follow-up. There were no significant differences in treatment-related complications between the two groups. The early postoperative (three and six months) effective percentage was not significantly different (P > 0.05). After 9 months, the postoperative effective rate for group A (9/15) was significantly different from that for group B (radiofrequency ablation) (6/15) (P < 0.05). Radiofrequency ablation combined with radiation 125I seed implantation can complement each other in the treatment of nonsmall cell lung cancer.

Cancer-driven IgG promotes the development of prostate cancer though the SOX2-CIgG pathway.

BACKGROUND: Although androgen deprivation therapy (ADT) is the initial treatment strategy for prostate cancer (PCa), recurrent castration-resistant prostate cancer (CRPC) eventually ensues. In this study, cancer-derived immunoglobulin G (CIgG) is found to be induced after ADT, identifying CIgG as a potential CRPC driver gene. METHODS: The expression of CIgG and its clinical significance in PCa tissue was analyzed by The Cancer Genome Atlas database and immunohistochemistry. Subsequently, the sequence features of prostate cell line VHDJH rearrangements were analyzed. We also assessed the effect of CIgG on the migratory, invasive and proliferative abilities of PCa cells in vitro and vivo. Suspended microsphere, colony formation and drug-resistant assays were performed using PC3 cells with high CIgG expression (CIgGhigh ) and low CIgG expression (CIgG-/low ), and A nonobese diabetic/severe combined immunodeficiency mouse tumor xenograft model was developed for the study of the tumorigenic effects of the different cell populations. The SOX2-CIgG signaling pathway was validated by immunohistochemistry, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, Western blot, luciferase, and chromatin immunoprecipitation assays and bioinformatics analyses. Finally, we investigated the effect of RP215 inhibition on the progression of PCa in vivo using a Babl/c nude mouse xenograft model. RESULTS: CIgG is frequently expressed in PCa and associated with clinicopathological characteristics, moreover, CIgG transcripts with unique patterns of VHDJH rearrangements are found in PCa cells. Functional analyses identified that CIgG was induced by ADT and upregulated by SOX2 (SRY (sex determining region Y)-box 2) in PCa, promoting the development of PCa. In addition, our findings underscore a novel role of CIgG signaling in the maintenance of stemness and the progression of cancer through mitogen activated protein kinase/extracellular-signal-regulated kinase and AKT in PCa. In vivo experiments further demonstrated that depleting CIgG significantly suppressed the growth of PCa cell xenografts. Furthermore, a CIgG monoclonal antibody named RP215 exhibits tumor inhibitory effect as well. CONCLUSION: Our data suggests that CIgG could be a driver of PCa development, and that targeting the SOX2-CIgG axis may therefore inhibit PCa development after ADT.

CMTM5-v1 inhibits cell proliferation and migration by downregulating oncogenic EGFR signaling in prostate cancer cells.

Anomalous epidermal growth factor receptor (EGFR) signaling plays an important role in the progression of prostate cancer (PCa) and the transformation to castration-resistant PCa (CRPC). A novel tumor suppressor CKLF-like MARVEL transmembrane domain-containing member 5(CMTM5) has a MARVEL domain and may regulate transmembrane signaling. Thus, we postulated that CMTM5 could regulate EGFR and its downstream molecules to affect the biological behaviors of PCa cells. In this study, we found that CMTM5 was expressed in benign prostatic hyperplasia (BPH) tissues but was undetectable in PCa cells. However, the EGFR was upregulated in PCa cells, especially in two metastatic CRPC cell lines, PC3 and DU145. Furthermore, ectopic expression of CMTM5-v1 suppressed cell proliferation and migration and p-EGFR levels. Further investigation revealed that restoration of CMTM5-v1 inhibited not only EGF-mediated proliferation but also chemotactic migration by EGF in PC3 and DU145 cells. Moreover, mechanistic studies showed that CMTM5-v1 attenuated EGF-induced receptor signaling by repressing EGFR and Akt phosphorylation in PCa cells, which were essential for malignant features. Finally, CMTM5-v1can promote the sensitivity of PC3 cells to Gefetinib, a tyrosine kinase inhibitor (TKI) targeting the EGFR. These observations indicate that CMTM5-v1 suppressed PCa cells through EGFR signaling. The loss of CMTM5 may participate in the progression of PCa resulting from deregulated EGFR, and CMTM5 might be associated with the efficacy of TKIs in terms of their potent inhibition of EGFR and human epidermal growth factor-2 (HER2) activation.

Oleic acid promotes cell invasion through an integrin-linked kinase signaling pathway in renal cell carcinoma.

The change of fatty acid composition has been regarded as an indicator of altered lipid metabolism during human tumourigenesis, but the details are still unclear. We have previously demonstrated a monounsaturated fatty acid (MUFA) named oleic acid (OA) was involved in renal cell carcinoma (RCC) cell growth, as an extracellular signaling molecule to regulate 786-O cell proliferation via the integrin-linked kinase (ILK) pathway. In this study, we further observe the effects of OA on cell invasion of RCC and the potential mechanism by which OA worked was determined. The transwell invasion assay showed OA increased cell invasion of RCC in a dose-dependent manner. Western blotting results indicated ILK, COX-2, and MMP-9 proteins were involved for their high expressions and these effects were reversed when down-regulating the expression of ILK by special siRNA. The MMPs inhibitor GM6001 could weaken the abilities of OA on RCC cells invasion. These results suggested MUFA indeed affected cell invasion of RCC, which was depended by the regulation of ILK pathway.

Lung squamous cell carcinoma cells express non-canonically glycosylated IgG that activates integrin-FAK signaling.

It is increasingly recognized that many human carcinomas express immunoglobulin (Ig) molecules that are distinct from B-cell-derived Ig and play important roles in cancer initiation, progression, and metastasis. However, the molecular mechanisms underlying the functions of cancer-derived Ig remain elusive. Here, we report that lung squamous cell carcinoma (LSCC) cells frequently express high levels of cancer IgG (CIgG) that is specifically recognized by a monoclonal antibody RP215. RP215 recognizes CIgG via a novel epitope that involves an N-glycan modification at a non-consensus site within the CH1 domain. We demonstrate that RP215 recognized CIgG (RP215-CIgG) promotes survival, migration and in vivo growth of LSCC cells, and these oncogenic activities are strongly inhibited by RP215. Mechanistically, RP215-CIgG executes its oncogenic function through interacting with the integrin α6ß4 complex and activating the FAK and Src pathways. Notably, the CIgG-integrin-FAK signaling depends on the N-glycan epitope, which is inhibited by RP215. Together, our studies identified a novel CIgG molecule that activates the oncogenic integrin-FAK signaling in LSCC cells. In addition, the activity of CIgG is inhibited by RP215, providing an attractive target for antibody-based therapy of LSCC.

Lysophosphatidylcholine acyltransferase 1 upregulation and concomitant phospholipid alterations in clear cell renal cell carcinoma.

BACKGROUND: The involvement of lipid metabolism in tumourigenesis and the progression of clear cell renal cell carcinoma (ccRCC) have been reported. However, the role of phospholipid profile alterations in ccRCC has not yet been systematically explored. In the present study, we compared the phospholipid compositions between ccRCC and paired normal renal tissues. METHODS: The phospholipid compositions of paired ccRCC and normal renal tissues were evaluated using liquid chromatography tandem mass spectrometry (LC/MS/MS). To evaluate the mRNA and protein levels of lysophosphatidylcholine acyltransferase (LPCAT), which converts lysophosphatidylcholine (LPC) to phosphatidylcholine (PC), qRT-PCR, western blotting and immunohistochemistry were performed. The correlations of LPCAT1 expression with clinicopathological features and prognosis were assessed. In addition, siRNAs were used to knockdown LPCAT1 expression in ccRCC cell lines, and its effect on cell proliferation, cell cycle, migration and invasion were investigated. RESULTS: The phospholipid compositions of ccRCC and normal renal tissues were significantly different. Multiple LPC species were decreased and corresponding PC species were increased in cancer tissues. The mRNA and protein levels of LPCAT1 were up-regulated in ccRCC tissues compared with normal renal tissues, and LPCAT1 expression was significantly correlated with unfavourable pathological features (higher tumour grade, higher TNM stage and larger tumour size) and overall survival. In cell line experiments, LPCAT1 knockdown depleted PCs, inhibited cell proliferation, migration and invasion and induced cell cycle arrest at the G0/G1 phase. CONCLUSION: Selective changes in PC and LPC composition were observed in ccRCC tissues. The overexpression of LPCAT1 promotes the development and progression of ccRCC, likely through the conversion of LPC to PC.

Overexpression of SOX18 promotes prostate cancer progression via the regulation of TCF1, c-Myc, cyclin D1 and MMP-7.

Sex determining region Y (SRY)-box 18 (SOX18) gene encodes transcription factors that have been recently confirmed to be overexpressed in various human types of cancer and maintain the malignant behavior of cancer cells. However, the role and its potential function in prostate cancer (PCa) has not been demonstrated and the mechanisms of SOX18 involved in tumor progression remain largely unclear. In the present study, the expression of SOX18 was analyzed in 98 PCa and 81 adjacent non-tumor tissues using immunohistochemistry. The data showed that SOX18 was overexpressed in 72 of 98 (73.5%) PCa tissues compared with that in 28 of 81 (34.6%) non-tumor tissues. In addition, the expression of SOX18 was related with the clinical features of patients with PCa. To explore the potential role of SOX18 in PCa cells, Cell Counting Kit-8 (CCK-8), migration, invasion and xenograft assays were performed. Our data showed that knockdown of SOX18 decreased the proliferation, migration and invasion of PCa cells in vitro, in addition to the tumor growth in vivo. Markedly, SOX18 knockdown caused the decreased expression of TCF1, c-Myc, cyclin D1 and MMP-7. In conclusion, SOX18 was overexpressed in PCa and may regulate the malignant capacity of cells via the upregulation of TCF1, c-Myc, cyclin D1 and MMP-7.

Research Advances in CKLFSF-like MARVEL Transmembrane Domain Containing Member 3.

CKLF-like MARVEL transmembrane domain containing member/chemokine-like factor super family member (CKLFSF/CMTM) is a novel tumor suppressor gene. CMTM3 is broadly expressed in normal human tissues and evolutionary conserved,especially in testis,spleen,and some cells of peripheral blood mononuclear cells. However,its expression is undetectable or down-regulated in most carcinoma cell lines and tissues. Restoration of CMTM3 may inhibit the proliferation,migration,and invasion of carcinoma cells. Although the exact mechanism of its anti-tumor activity remains unclear,CKLFSF3/CMTM3 is closely connected with immune system and associated with sex during tumorigenesis. The study advances of CKLFSF3/CMTM3 are elaborated in this review as CMTM3 may be a new target in the gene therapies for tumors,especially genitourinary tumors,while further studies on CMTM3 and its anti-tumor mechanisms are warranted.

IgG is involved in the migration and invasion of clear cell renal cell carcinoma.

OBJECTIVE: To investigate if IgG can be expressed in clear cell renal cell carcinoma (cRCC) , and the expression of IgG is involved in the cancer progression. If IgG expression can serve as a potential target in cancer therapies and be used for judging the prognosis. MATERIALS AND METHODS: By immunohistochemistry, we detected IgG in cRCC tissues(75 cRCC tissues and75 adjacent normal kidney tissues). Immunofluorescence and Western blot was used to detect the IgG in cRCC cell lines (786-0, ACHN and CAKI-I). By RT-PCR, the functional transcript of IgG heavy chain was detected. Knockdown of IgG was to analyze the proliferation, migration and invasion ability by CCK8, Transwell and Matrigel and apoptosis in cRCC cell lines. RESULTS: By immunohistochemistry, we found strong staining of IgG in 66 cases of 75 cRCC tissues and 63 cases of 75 adjacent normal kidney tissues. Immunofluorescence and Western blot was found IgG in cRCC cell lines. Knock-down IgG in cRCC cell lines resulted in significant inhibition of cell proliferation, migration and invasion, and the induction of apoptosis of the 786-0 cells. The immunohistochemistry analysis showed that high IgG expression significantly correlated with the poor differentiation and advanced stage of cRCC. CONCLUSION: IgG was over expressed in cRCC and was involved in the proliferation, migration and invasion of cancer cells. IgG expression may serve as a potential target in cancer therapies and could be used for judging the prognosis.

Involvement of cancer-derived IgG in the proliferation, migration and invasion of bladder cancer cells.

It is widely accepted that immunoglobulin (Ig), the classical immune molecule, is extensively expressed in many cell types other than B-cells (non-B-IgG), including some malignant cells. The expression of Ig in malignant cells has been associated with a poor prognosis. In the present study, immunohistochemical analysis detected strong positive staining of IgG in three bladder cancer cell lines, the cancer cells in 77 bladder cancer patient samples and the cells in 3 cystitis glandularis tissue samples, while negative staining was observed in 4 specimens of normal transitional epithelial tissues. Importantly, functional transcripts of IgG with unique VHDJH rearrangement patterns were also found in bladder cancer cells. The knockdown of IgG in bladder cancer cell lines using small interfering RNA significantly inhibited the proliferation, migration and invasion of the cells. Notably, high IgG expression, as determined by immunostaining, was significantly correlated with a high histological grade and recurrence. The results of the present study suggested that IgG expression is involved in the malignant biological behavior and poor prognosis of bladder cancer. Therefore, IgG may serve as a novel target for bladder cancer therapy.

[Expression of glycoprotein non-metastatic melanoma protein B in clear-cell renal cell carcinoma and clinical implication thereof].

OBJECTIVE: To elucidate the glycoprotein non-metastatic melanoma protein B(Gpnmb) expression in clear-cell renal cell carcinoma (ccRCC) and to determine its potential prognostic relevance. METHODS: A total of 12 pairs of ccRCC tissue specimens were collected from patients undergoing surgery in our hospital from March 2009 to March 2012. Gpnmb expression were determined by immunohistochemistry and correlated with clinical variables. Survival analysis was carried out for another 43 evaluable patients. RESULTS: The expression level of Gpnmb was significantly higher in metastatic ccRCCs than that in matched primary samples ((6.36±4.01) vs (3.14±2.38) scores, P=0.036). The high expression of Gpnmb was not affected by age, gender, clinical stage and pathological grade (all P>0.05). Kaplan-Meier analysis disclosed significant differences in overall survival for patients with higher and lower average Gpnmb expression levels (P=0.020). Cox regression analysis revealed that a high Gpnmb protein expression level in the tumor cell could be identified as an independent poor prognostic marker of overall survival in ccRCC patients (P=0.049). CONCLUSION: Over expression of Gpnmb in tumour cell predicts a poor prognosis of patients with ccRCC.

Aberrant high expression of immunoglobulin G in epithelial stem/progenitor-like cells contributes to tumor initiation and metastasis.

High expression of immunoglobulin G (IgG) in many non-B cell malignancies and its non-conventional roles in promoting proliferation and survival of cancer cells have been demonstrated. However, the precise function of non-B IgG remains incompletely understood. Here we define the antigen specificity of RP215, a monoclonal antibody that specifically recognizes the IgG in cancer cells. Using RP215, our study shows that IgG is overexpressed in cancer cells of epithelial lineage, especially cells with cancer stem/progenitor cell-like features. The RP215-recognized IgG is primarily localized on the cell surface, particularly lamellipodia-like structures. Cells with high IgG display higher migration, increased invasiveness and metastasis, and enhanced self-renewal and tumorgenecity ability in vitro and in vivo. Importantly, depletion of IgG in breast cancer leads to reduced adhesion, invasion and self-renewal and increased apoptosis of cancer cells. We conclude that high expression of IgG is a novel biomarker of tumor progression, metastasis and cancer stem cell maintenance and demonstrate the potential therapeutic benefits of RP215-recognized IgG targeted strategy.

[Expression and significance of CMTM5 and epidermal growth factor receptor in prostate cancer].

OBJECTIVE: To investigate the expression patterns of CKLF-like MARVEL transmembrane domain containing 5 (CMTM5), a novel tumor suppressor, and epidermal growth factor receptor (EGFR) in prostate cancer (PCa) tissues and cells and to analyze the relationship between CMTM5 and EGFR in PCa. METHODS: The expression patterns of CMTM5 and EGFR in PCa tissues and cells were detected by immunohistochemistry and Western blot, respectively. RESULTS: CMTM5 was highly expressed in 75% (27/36) of benigh prostatic hyperplasia (BPH) tissues but 35.9% (23/64) of PCa tissues (P<0.001). There was a significant difference of CMTM5 expression between the two groups of PCa tissues with different Gleason scores (P=0.003), though its expression was not related to the age, clinical stage, and metastatic situation (P>0.05). EGFR was highly expressed in 57.8% (37/64) of PCa tissues, it had statistical significance between EGFR and CMTM5 expressions in PCa tissues. Furthermore, 23 cases (35.9%) had low CMTM5 expression and high EGFR expression. Western blot showed that CMTM5 was undetectable in PCa cells, in which the EGFR expression was upregulated. CONCLUSION: The loss of CMTM5 may participate in the progression of PCa resulting from deregulated EGFR.

[Clinical characteristics of IgG4 related retroperitoneal fibrosis: a report of 5 cases and literature review].

OBJECTIVE: To explore the clinical characteristics, treatment and prognosis of IgG4-related retroperitoneal fibrosis (RPF). METHODS: All the patients diagnosed as RPF in Peking University People's Hospital between February 2008 and October 2014 were included. Among them, 5 patients were identified as IgG4 related RPF. We analyzed their medical records and summarized the clinical, laboratory, and imaging features of IgG4 related RPF, which had taken the recent literature into account. RESULTS: All the 5 patients were male, with the average age 62.2 years (55-67 years). They mainly complained of abdominal pain, flank pain and weight loss, two of whom had concurrent antoimmune pancreatitis. Renal insufficiency was present in 3 patients (3/5). Four patients (4/4) showed increased erythrocyte sedimentation rate (ESR), while 3 patients (3/4) had higher serum C-reactive protein (CRP) and IgG. In addition, 4 patients (4/4) had significantly elevated serum IgG4 level. On computed tomography (CT) imaging, 5 patients showed retroperitoneal mass which surrounded the abdominal aorta and the iliac arteries, and even enveloped the ureters and the inferior vena cava. Only one patient received tissue pathological examination, which indicated the numbers of IgG4-positive plasma cells per high power field>10 and a ratio of IgG4-positive cells to all IgG-bearing cells>40%. One patient received simple surgical intervention, and 1 patient received medical treatment alone, while the remaining 3 patients received combined treatment of surgery and medications. follow-up was available for the 4 patients, all of whom had good prognosis. CONCLUSION: Part of RPF was actually IgG4-related, which was also nominated as IgG4 related RPF. It was a rare disease with unknown etiology, characterized by the elevated serum IgG4 concentration (≥1.35 g/L), with marked tissue infiltration by lymphocytes and IgG4-positive plasma cells with fibrosis, in addition to the presence of retroperitoneal mass. Glucocorticoids were the first-line therapy and IgG4 related RPF had a favourable prognosis.