Serum neopterin concentrations during treatment of leishmaniasis: useful as test of cure?

Neopterin, a product of gamma-interferon-activated macrophages, was measured in sera from 28 patients (12 patients with cutaneous leishmaniasis and 16 patients with visceral leishmaniasis) to determine the utility as a marker of disease activity and therapeutic efficacy. Patients originated from Kenya (n=5) and from the Academic Medical Center, Amsterdam, The Netherlands (n=23). In seven patients follow-up sera after treatment were available. Two patients at the time of diagnosis of visceral leishmaniasis were co-infected with HIV. The 12 patients with cutaneous leishmaniasis had serum neopterin levels below the upper limit of the normal range. All 16 patients with visceral leishmaniasis had elevated levels of serum neopterin before treatment. In six out of seven patients with visceral leishmaniasis followed during treatment neopterin levels decreased to values below the upper limit of the normal range (10 nmol l(-1)). Sequential measurements of serum neopterin levels may be useful for monitoring therapeutic efficacy in patients with visceral leishmaniasis.     

Copper and zinc metabolism with solid tumor growth

The variation in copper and zinc metabolism with tumor growth appears to relate directly to progression or regression of the disease. Historically, elevations in serum copper have been used as clinical indicators in hematological neoplasms since the early 1960s. More recently, we have monitored breast, colo-rectal, and lung cancer patients for a six-month period through courses of cytotoxic chemotherapy to determine copper and zinc changes with tumor growth. Groups were divided into responders and nonresponders blind to their serum copper and zinc levels. Trends in elevated serum copper with active disease have shown similar trends in decreasing values with effective therapy, but normalization was at a slower rate. Serum zinc levels in the same patients were markedly below normal and did not increase in the study period. The clinical significance or elevated serum copper and depressed serum zinc is discussed and the potential relationship between the two elements is explored. A solid tumor-bearing rat model, mammary adenocarcinoma R 3230 AC, has detailed more of the changes in copper and zinc metabolism with solid tumor growth. Serum copper and zinc varied with tumor mass, as in clinical studies. Liver values of the two essential metals did not change significantly, but liver-related copper-containing enzymes showed marked variations. Ceruloplasmin in serum increased with increasing tumor mass, as would be expected with the increased serum copper levels. Cytochrome c oxidase activity in liver homogenates from tumor-bearing animals was significantly depressed.     

乳腺癌患者血清内IL-6 和CCL-18表达及其与临床病理因素的关系

目的:探究乳腺癌患者血清内白细胞介素-6(IL-6)和趋化因子配体-18(CCL-18)表达水平及其与临床病理因素的关系。方法:本研究于2014年4月~2015年4月期间,选择我院收治31例乳腺癌患者(乳腺癌组)、29例良性肿瘤患者(良性肿瘤组)与30例健康体检者(对照组)为研究对象,采用酶联免疫吸附试验(ELISA)法测定所有研究对象的血清IL-6与CCL-18水平,采用免疫组化法检测患者的临床病理参数。结果:乳腺癌组患者血清IL-6和CCL-18水平均显著高于良性肿瘤组和对照组,良性肿瘤组血清IL-6和CCL-18水平高于对照组,差异均有统计学意义(P0.05);血清IL-6S水平与雌激素受体(ER)、肿瘤增殖抗原(Ki67)、肿瘤TNM分期及淋巴转移存在关联(P0.05),血清CCL-18水平与Ki67与肿瘤TNM分期存在关联(P0.05)。结论:IL-6和CCL-18在乳腺癌患者内出现高表达,且均可预示患者肿瘤的发展恶化,影响预后。     

Transforming growth factor beta 1 serum levels in patients with preinvasive and invasive lesions of the breast

Transforming growth factor beta (TGF-beta)1 is thought to be involved in breast carcinogenesis. TGF-beta1 acts in an antiproliferative manner in the early stages of breast carcinogenesis, but promotes tumor progression and metastases in the advanced stages of the disease. No data have been published on serum TGF-beta1 in breast cancer. We investigated TGF-beta1 serum levels in patients with breast cancer (n=135), ductal carcinoma in situ (DCIS) I to III (n=67) or fibroadenoma (n=35), and in healthy women (n=40) to determine its value as a differentiation marker between malignant, pre-invasive and benign diseases and as a predictive marker for metastatic spread. Median (range) TGF-beta1 serum levels in patients with breast cancer, DCIS I-III or benign breast lesions and in healthy women were 48.8 (18-82.4) pg/mL, 45.3 (26.9-58.3) pg/mL, 47.2 (17.2-80.5) pg/mL and 51.6 (30.9-65.1) pg/mL, respectively (p=0.2). In breast cancer patients TGF-beta1 serum levels showed no statistically significant correlation with tumor stage, lymph node involvement, histological grade, estrogen receptor status and progesterone receptor status. Our data fail to indicate any correlation between serum TGF-beta1 levels and clinicopathological parameters of breast diseases. Serum TGF-beta1 levels do not provide clinical information in addition to established tumor markers.     

OLFM4 Expression in Ductal Carcinoma In Situ and in Invasive Breast Cancer Cohorts by a SWATH‐Based Proteomic Approach

Human olfactomedin‐4 (OLFM4) is a secreted protein involved in a variety of cellular functions including proliferation, differentiation, apoptosis, and cell adhesion. OLFM4 expression has been studied in several tumor types including gastric, colorectal, lung, and endometrioid cancers where it has been suggested to be an independent favorable or unfavorable prognostic marker. For breast cancer, the clinical significance of OLFM4 is still unclear. In the present study, SWATH‐MS is used as a tool for the robust identification and quantification of breast tissue proteins. SWATH‐MS data show that OLFM4 expression is higher in DCIS than in invasive breast cancer. In‐depth analysis of the breast tumor proteome show that OLFM4 is a favorable pronostic marker. Serum OLFM4 levels in peripheral blood are also analyzed by ELISA in 825 cases, including 94 cases of healthy individuals, 61 cases of non‐invasive breast tumor (DCIS) and 670 cases of breast cancer (BC). It is found that serum OLFM4 levels are significantly higher in the DCIS cohort and in the breast cancer cohort compared with the healthy controls. This result suggests that circulating OLFM4 could be an interesting biomarker of early breast cancer. Data are available via ProteomeXchange with identifier PXD014194.     

Elimination of breast tumor-associated chondroitin sulfate promotes metastasis

Breast cancer is one of the leading causes of cancer-related deaths amongst women in the USA. The tumor microenvironment has been suggested to be an attractive therapeutic target for treatment of cancers. The glycosaminoglycan chondroitin sulfate, as part of the cellular microenvironment, consists of long linear chains of repeating disaccharide units, which are covalently attached to core proteins to form chondroitin sulfate-proteoglycans. In vitro studies have implicated chondroitin sulfate in various aspects of carcinogenesis, whereas the in vivo roles of chondroitin sulfate are less clear. Drastically elevated levels of chondroitin sulfate have been observed within the stromal compartment of many solid tumors, including human breast carcinomas, the significance of which is unknown. We examined the role of tumor-associated chondroitin sulfate in breast cancer progression. Enzymatic elimination of endogenous chondroitin sulfate by intra-tumor injections of chondroitinase ABC leads to the development of secondary tumors and increased lung metastases, while primary orthotopic tumor growth was not affected. These results establish a metastasis-inhibiting effect of primary breast tumor-associated chondroitin sulfate, which may open novel carbohydrate-based therapeutic strategies to combat breast cancer.     

Role of adipokines and cytokines in obesity-associated breast cancer: Therapeutic targets

Obesity is the cause of a large proportion of breast cancer incidences and mortality in post-menopausal women. In obese people, elevated levels of various growth factors such as insulin and insulin-like growth factors (IGFs) are found. Elevated insulin level leads to increased secretion of estrogen by binding to the circulating sex hormone binding globulin (SHBG). The increased estrogen-mediated downstream signaling favors breast carcinogenesis. Obesity leads to altered expression profiles of various adipokines and cytokines including leptin, adiponectin, IL-6, TNF-α and IL-1β. The increased levels of leptin and decreased adiponectin secretion are directly associated with breast cancer development. Increased levels of pro-inflammatory cytokines within the tumor microenvironment promote tumor development. Efficacy of available breast cancer drugs against obesity-associated breast cancer is yet to be confirmed. In this review, we will discuss different adipokine- and cytokine-mediated molecular signaling pathways involved in obesity-associated breast cancer, available therapeutic strategies and potential therapeutic targets for obesity-associated breast cancer.     

CEA determination in the follow-up of extracolorectal neoplasms.

CEA was initially described as a tumor and organ specific colorectal antigen, but later found by more sensitive methods in other tumors (stomach, pancreas, lung, breast) and in minor amounts in inflammatory, normal adult and fetal organs of the gastrointestinal tract. The main clinical application of CEA concerns its pretherapeutic and serial determination as circulating antigen in serum and other body fluids by means of CEA-specific, commercially available test kits. By clinical studies a significant correlation has been proven between the pretherapeutic serum CEA level and tumor stages and prognosis. Moreover, serial CEA level changes have been shown a valuable monitor following operation or during radio/chemotherapy anticipating and reflecting the clinical course of disease. In combination with newly established tumor markers, the main clinical indication for CEA determination in addition to colorectal cancer concerns monitoring of patients with stomach (+CA 72-4), lung (+NSE/SCC) and breast cancer (+CA 15-3/MCA).     

Claudin-2 promotes breast cancer liver metastasis by facilitating tumor cell interactions with hepatocytes

We previously identified claudin-2 as a functional mediator of breast cancer liver metastasis. We now confirm that claudin-2 levels are elevated in liver metastases, but not in skin metastases, compared to levels in their matched primary tumors in patients with breast cancer. Moreover, claudin-2 is specifically expressed in liver-metastatic breast cancer cells compared to populations derived from bone or lung metastases. The increased liver tropism exhibited by claudin-2-expressing breast cancer cells requires claudin-2-mediated interactions between breast cancer cells and primary hepatocytes. Furthermore, the reduction of the claudin-2 expression level, either in cancer cells or in primary hepatocytes, diminishes these heterotypic cell-cell interactions. Finally, we demonstrate that the first claudin-2 extracellular loop is essential for mediating tumor cell-hepatocyte interactions and the ability of breast cancer cells to form liver metastases in vivo. Thus, during breast cancer liver metastasis, claudin-2 shifts from acting within tight-junctional complexes to functioning as an adhesion molecule between breast cancer cells and hepatocytes.     

Urinary pS2/TFF1 levels in the management of hormonodependent breast carcinomas

pS2/TFF1 overexpression in breast carcinomas correlates with response to hormonotherapy. We evaluated the clinical relevance of urinary pS2/TFF1 in breast cancer patients. In healthy controls (100 cases), it represents an individual and relatively stable parameter. Although 24 out 83 pre-operative breast cancer patients showed elevated levels, both the sensitivity and specificity of the test were too low for breast cancer screening. However, neoadjuvant hormonotherapy decreased pS2/TFF1 levels in nine out of 20 patients. Furthermore, among 22 patients receiving long-term adjuvant hormonotherapy, four exhibited elevated levels, two of them at the time of relapse. Thus, urinary pS2/TFF1 quantification might be suitable as an in vivo diagnosis for tumor hormonodependency, and disease follow-up during hormonotherapy.     

The mitochondrial protein C1qbp promotes cell proliferation,migration and resistance to cell death

Complement 1q-binding protein (C1qbp) is a mitochondrial protein reported to be upregulated in cancer. However, whether C1qbp plays a tumor suppressive or tumorigenic role in the progression of cancer is controversial. Moreover, the exact effects of C1qbp on cell proliferation, migration and death/survival have not been definitely proven. To this end, we comprehensively examined the effects of C1qbp on mitochondrial-dependent cell death, proliferation and migration in both normal and breast cancer cells using genetic gain- and loss-of-function approaches. In normal fibroblasts, overexpression of C1qbp protected the cells against staurosporine-induce apoptosis, increased proliferation, decreased cellular ATP and increased cell migration in a wound-healing assay. In contrast, the opposite effects were observed in fibroblasts depleted of C1qbp by RNA interference. C1qbp expression was found to be markedly elevated in 4 different human breast cancer cell lines as well as in ductal and adenocarcinoma tumors from breast cancer patients. Stable knockdown of C1qbp by shRNA in the aggressive MDA-MB-231 breast cancer cell line greatly reduced cell proliferation, increased ATP levels and decreased cell migration compared with control shRNA-transfected cells. Moreover, C1qbp knockdown elicited a significant increase in doxorubicin-induced apoptosis in the MDA-MB-231 cells. Finally, C1qbp upregulation was not restricted to breast cancer cells and tumors, as levels of C1qbp were also found to be significantly elevated in both human lung and colon cancer cell lines and carcinomas. Together, these results establish a pro-tumor, rather than antitumor, role for C1qbp and indicate that C1qbp could serve as a molecular target for cancer therapeutics.Key words: mitochondria, cell proliferation, cell migration, cell death, tumor cells     

The mitochondrial protein C1qbp promotes cell proliferation,migration and resistance to cell death

Complement 1q-Binding Protein (C1qbp) is a mitochondrial protein reported to be upregulated in cancer. However, whether C1qbp plays a tumor suppressive or tumorigenic role in the progression of cancer is controversial. Moreover, the exact effects of C1qbp on cell proliferation, migration, and death/survival have not been definitely proven. To this end, we comprehensively examined the effects of C1qbp on mitochondrial-dependent cell death, proliferation, and migration in both normal and breast cancer cells using genetic gain- and loss-of-function approaches. In normal fibroblasts, overexpression of C1qbp protected the cells against staurosporine-induce apoptosis, increased proliferation, decreased cellular ATP, and increased cell migration in a wound-healing assay. In contrast, the opposite effects were observed in fibroblasts depleted of C1qbp by RNA interference. C1qbp expression was found to be markedly elevated in 4 different human breast cancer cell lines as well as in ductal and adenocarcinoma tumors from breast cancer patients. Stable knockdown of C1qbp by shRNA in the aggressive MDA-MB-231 breast cancer cell line greatly reduced cell proliferation, increased ATP levels, and decreased cell migration compared to control shRNA-transfected cells. Moreover, C1qbp knockdown elicited a significant increase in doxorubicin-induced apoptosis in the MDA-MB-231 cells. Finally, C1qbp upregulation was not restricted to breast cancer cells and tumors, as levels of C1qbp were also found to be significantly elevated in both human lung and colon cancer cell lines and carcinomas. Together, these results establish a pro-tumor, rather than anti-tumor, role for C1qbp, and indicate that C1qbp could serve as a molecular target for cancer therapeutics.     

Cysteine proteinases and their inhibitors in extracellular fluids: markers for diagnosis and prognosis in cancer

Cathepsins B, H and L have been shown to participate in processes of tumor growth, vascularization, invasion and metastasis. Their levels in tumor tissue extracts can provide useful clinical information to predict disease-free and overall survival in breast, lung, colorectal, brain and head and neck cancer patients. Recently we have found that both cysteine cathepsins and their endogenous protein inhibitors stefins and cystatin C can also predict prognosis when measured extracellularly. In melanoma and colorectal cancer patients high serum levels of cathepsins B and H correlated with shorter survival. Similarly, increased extracellular levels of stefins A and B and cystatin C correlated significantly with high risk of adverse outcome in cancer patients. However, the cathepsin B/cystatin C complex was found to be less abundant in sera of patients with malignant tumors than in those with benign diseases or in healthy controls, suggesting an imbalance between the enzyme and its inhibitor in cancer patients.     

Which immunological parameters are clinically essential to monitor IL-2 cancer immunotherapy?

The evaluation of the immunobiological changes occuring during IL-2 cancer immunotherapy is not only important to correlate them with the clinical response or to understand the immune mechanism involved in tumor growth control, but also to predict the efficacy of treatment itself. As far as the immune status of patients prior to therapy is concerned, the evidence of the activation of the inflammatory response correlates with resistance to IL-2. Therefore, the evidence of abnormally high pretreatment values of inflammatory response markers, including ESR, CRP, neopterin and SIL-2R, may predict a lack of IL-2 efficacy. In contrast, changes in inflammatory parameters during IL-2 administration have no prognostic significance. The evidence of elevated pretreatment levels of the immunosuppressive cytokine IL-10 has also an unfavourable prognostic significance. At the other side, the evidence of a marked increase in hemopoietic cells involved in tumor cell destruction, such as lymphocytes and eosinophils, as well as in blood levels of antitumor cytokines, such as IL-12, correlates with efficacy of IL-2 cancer immunotherapy. A better definition of the prognostic significance of immunoinflammatory markers will allow us to manipulate and improve host biological response during cancer immunotherapy with IL-2.     

The prognostic value of the tumor marker CA 15-3 at initial diagnosis of patients with breast cancer

CA 15-3 has been most widely used as a serum tumor marker in follow-up and detection of breast cancer recurrence. In this study we have specifically focused upon the prognostic implications and utility of preoperative CA 15-3 levels. We have identified on our database 414 patients with breast cancer in whom serial levels of the serum tumor marker CA 15-3 had been determined at diagnosis and follow-up. We have analyzed the follow-up and clinical outcomes in these patients and from this data we have assessed the potential of CA 15-3 as a predictor of five-year overall and disease-free survival. Our results show that an initially elevated CA 15-3 level is associated with a very poor prognosis in both early and late stage disease. Elevated pre-biopsy CA 15-3 levels are associated with 14% five-year disease-free survival rates and 17% overall survival rates at five years. In contrast, normal CA 15-3 levels are associated with 47% five-year disease-free survival rates and 54% overall survival rates at five years (p<0.01). Comparison of five-year survival rates between patients with elevated and normal CA 15-3 levels in early breast cancer (stage I and II) also showed significant differences, with survival being 41% and 75%, respectively (p<0.01).     

Changes in circulating VEGF levels in relation to clinical response during chemotherapy for metastatic cancer

Abnormally high blood levels of vascular endothelial growth factor (VEGF) appear to be associated with a poor prognosis in advanced cancer, probably as a consequence of its angiogenic and immunosuppressive effects. The prognostic significance of changes in VEGF secretion during cancer chemotherapy is still unknown. This study aimed to investigate the relation between VEGF variations and therapeutic results during chemotherapy in advanced malignancies. The study included 90 metastatic cancer patients, 59 with non-small cell lung cancer and 31 with colorectal carcinoma. Chemotherapy consisted of cisplatin plus etoposide for NSCLC and camptothecin for colorectal cancer. Abnormally high (> 2 SD with respect to values in healthy controls) pretreatment VEGF levels were found in 38/90 (42%) patients. The percentage of non-progressive disease in response to chemotherapy was significantly higher in patients with normal levels of VEGF prior to therapy than in those with elevated pretreatment values of VEGF (10/32 vs 4/27; p < 0.05). Moreover, the percentage of VEGF level normalization during chemotherapy was significantly higher in patients with objective tumor response or stable disease than in progressing patients (10/18 vs 0/20; p < 0.001). Finally, among patients with tumor response or disease stabilization, the one-year survival rate was significantly higher in patients with chemotherapy-induced normalization of VEGF than in those with persistently high VEGF blood levels (9/10 vs 3/8; p < 0.05). These results suggest that changes in VEGF levels during chemotherapy may represent a useful biomarker to predict the effect of chemotherapy in terms of tumor response and survival in patients with metastatic solid neoplasms.     

Evaluation of chromogranin A expression in serum and tissues of breast cancer patients

Human chromogranin A (CgA) is a member of the granin family and is widely distributed in large dense core granules of endocrine and neuroendocrine cells. A variety of non-neuroendocrine carcinomas arising in various tissues show patterns of neuroendocrine differentiation. Expression of CgA has been documented in epithelial cells of normal mammary gland as well as in breast cancers, and elevation of serum CgA has been detected in patients with breast cancer. Our study was undertaken to evaluate the relationship between serum CgA levels and neuroendocrine features in breast cancer. In addition, we evaluated the expression of serum CgA in patients affected by breast cancer compared to controls and the relationship between serum CgA and tumor histology, extent of disease, lymph node status, tumor stage and serum CA 15.3 levels. We enrolled 266 patients with infiltrating ductal or lobular breast carcinoma and a group of 100 age-matched healthy women serving as controls. Serum CgA and CA 15.3 were assayed by specific immunoradiometric methods. The overall sensitivity of CgA and CA 15.3 was 0.06 and 0.34, respectively (chi2 19.1, p<0.0005). No relationship was found between serum levels of CgA and tumor histology, extent of disease, lymph node status or tumor stage while serum levels of CA 15.3 were strongly correlated with all these variables but tumor histology. No relationship was found between serum levels of CgA and CA 15.3. Immunostaining against CgA, CgB, NSE and synaptophysin was performed on primary tumor tissue of 14 serum CgA-positive and 24 serum CgA-negative patients and was negative in all cases. We also evaluated eight cases of pathologically-proven neuroendocrine breast cancer: only four and two of these showed positive CgA immunostaining and increased serum CgA concentration, respectively. In conclusion, serum CgA assay offers no additional information regarding the presence, the extent and the histology of breast cancer compared to the CA 15.3 assay. Moreover, serum CgA was not an accurate marker to identify or exclude the rare neuroendocrine differentiation of breast cancer. We therefore conclude that CgA is not useful as a serum marker in breast cancer.     

Somatostatin analogues in the treatment of breast and prostate cancer

Newly developed somatostatin analogues may be useful agents in the treatment of breast and prostate cancer. Potential mechanisms of antitumor action include suppression of circulating levels of trophic hormones and growth factors as well as direct effects at the tumor level, potentially involving autocrine/paracrine mechanisms. Pilot clinical trials conducted in heavily pretreated women with advanced breast cancer indicate that SMS 201–995 (Sandostatin®) has minimal toxicity and moderately suppresses stimulated growth hormone secretion and basal somatomedin-C level. Somatostatin analogues have also been found to retard the growth of experimental prostate cancer, particularly when used in combination with LHRH analogues. The therapeutic efficacy of these compounds used alone or in combination with other agents in the treatment of breast and prostate cancer remains to be established in larger clinical trials involving less heavily pretreated patients.     

Lipid peroxidation and antioxidant status in blood and tissue of malignant breast tumor and benign breast disease

Changes in the levels of malondialdehyde (MDA), nitrate and nitrite (as an index of nitric oxide production), lipid hydroperoxide (LOH), total antioxidant capacity (TAC), lipids (total cholesterol and triglycerides) and lipoproteins (HDL- and LDL-cholesterol) were estimated in breast cancer patients (n = 15) and benign breast disease (n = 15). Serum and tissue MDA levels were found to be decreased in breast cancer patients compared to the benign group (p < 0.05). In contrast, nitrate and nitrite levels were increased in serum and tissue of the cancer group compared to benign breast disease patients (p < 0.05). Compared to the benign group, tissue TAC levels were elevated in the breast cancer patient group (p < 0.05). Total cholesterol and HDL-cholesterol were elevated in the benign group compared with cancer patients (p < 0.05). These findings support the hypothesis that lipid peroxidation in serum and tissue of benign breast disease is greater than in breast cancer. However, the enhanced levels of nitric oxide may be in response to inflammation in patients with breast cancer. Total antioxidant status is lower in benign tissue than in cancerous tissue, probably to compensate for this elevated free radical production.     

Serum immunoglobulins in patients with carcinoma of the oral cavity,uterine cervix and breast

Summary Serum immunoglobulin levels (IgG, IgA, IgM, IgD and IgE) were estimated in 196 patients with carcinoma of the oral cavity, 172 patients with cervical cancer and 166 patients with breast cancer. The values were compared with those of 50 patients with benign lesions of the breast and cervix and 100 healthy adult controls. Only the serum IgE levels were found to be elevated in the benign group. Serum IgA, IgD and IgE levels were found to be elevated in all the three types of cancers and the levels were found to increase with clinical stage. In carcinoma of uterine cervix IgG levels were also found to be elevated. Immunoglobulins A and D returned to normal after clinical cure whereas IgE remained slightly elevated. IgD and IgE remained high in patients who had residual cancer.