Targeting of surface alpha-enolase inhibits the invasiveness of pancreatic cancer cells.

Pancreatic Ductal Adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by rapid progression, invasiveness and resistance to treatment. We have previously demonstrated that most PDAC patients have circulating antibodies against the glycolytic enzyme alpha-enolase (ENO1), which correlates with a better response to therapy and survival. ENO1 is a metabolic enzyme, also expressed on the cell surface where it acts as a plasminogen receptor. ENO1 play a crucial role in cell invasion and metastasis by promoting plasminogen activation into plasmin, a serine-protease involved in extracellular matrix degradation. The aim of this study was to investigate the role of ENO1 in PDAC cell invasion. We observed that ENO1 was expressed on the cell surface of most PDAC cell lines. Mouse anti-human ENO1 monoclonal antibodies inhibited plasminogen-dependent invasion of human PDAC cells, and their metastatic spreading in immunosuppressed mice was inhibited. Notably, a single administration of Adeno-Associated Virus (AAV)-expressing cDNA coding for 72/1 anti-ENO1 mAb reduced the number of lung metastases in immunosuppressed mice injected with PDAC cells. Overall, these data indicate that ENO1 is involved in PDAC cell invasion, and that administration of an anti-ENO1 mAb can be exploited as a novel therapeutic option to increase the survival of metastatic PDAC patients.

Three are better than one: plasminogen receptors as cancer theranostic targets.

Activation of plasminogen on the cell surface initiates a cascade of protease activity with important implications for several physiological and pathological events. In particular, components of the plasminogen system participate in tumor growth, invasion and metastasis. Plasminogen receptors are in fact expressed on the cell surface of most tumors, and their expression frequently correlates with cancer diagnosis, survival and prognosis. Notably, they can trigger multiple specific immune responses in cancer patients, highlighting their role as tumor-associated antigens. In this review, three of the most characterized plasminogen receptors involved in tumorigenesis, namely Annexin 2 (ANX2), Cytokeratin 8 (CK8) and alpha-Enolase (ENOA), are analyzed to ascertain an overall view of their role in the most common cancers. This analysis emphasizes the possibility of delineating new personalized therapeutic strategies to counteract tumor growth and metastasis by targeting plasminogen receptors, as well as their potential application as cancer predictors.

An integrated humoral and cellular response is elicited in pancreatic cancer by alpha-enolase, a novel pancreatic ductal adenocarcinoma-associated antigen.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with a very poor 5-year survival rate. alpha-Enolase is a glycolytic enzyme that also acts as a surface plasminogen receptor. We find that it is overexpressed in PDAC and present on the cell surface of PDAC cell lines. The clinical correlation of its expression with tumor status has been reported for lung and hepatocellular carcinoma. We have previously demonstrated that sera from PDAC patients contain IgG autoantibodies to alpha-enolase. The present work was intended to assess the ability of alpha-enolase to induce antigen-specific T cell responses. We show that alpha-enolase-pulsed dendritic cells (DC) specifically stimulate healthy autologous T cells to proliferate, secrete IFN-gamma and lyse PDAC cells but not normal cells. In vivo, alpha-enolase-specific T cells inhibited the growth of PDAC cells in immunodeficient mice. In 8 out of 12 PDAC patients with circulating IgG to alpha-enolase, the existence of alpha-enolase-specific T cells was also demonstrated. Taken as a whole, these results indicate that alpha-enolase elicits a PDAC-specific, integrated humoral and cellular response. It is thus a promising and clinically relevant molecular target candidate for immunotherapeutic approaches as new adjuvants to conventional treatments in pancreatic cancer.

Lactoferrin, a major defense protein of innate immunity, is a novel maturation factor for human dendritic cells.

Lactoferrin (LF) is an important protein component of the innate immune system that is broadly distributed within the body fluids. LF is endowed with multiple biological activities. Talactoferrin (TLF), a recombinant human LF, is in clinical development as an anticancer agent and is entering Phase III clinical trials. Here, we show that TLF induces the maturation of human dendritic cells (DCs) derived from monocytes. TLF, at physiologically relevant concentrations (100 microg/ml) up-regulates the expression of human leukocyte antigen (HLA) class II, CD83, CD80, and CD86 costimulatory molecule and CXCR4 and CCR7 chemokine receptors, acting primarily through the p38 MAPK signaling pathway. DCs matured by TLF displayed an enhanced release of IL-8 and CXCL10, as well as a significantly reduced production of IL-6, IL-10, and CCL20. They also display a reduced ability to take up antigen and increased capacity to trigger proliferation and release IFN-gamma in the presence of allogeneic human T cells. TLF-matured DCs are able to prime naive T cells to respond to KLH antigen and display a significantly increased capacity to present Flu-MA(58-66) peptide to HLA-A2-matched T cells. These data suggest that a key immunomodulatory function that may be mediated by TLF is to link the innate with adaptive immunity through DC maturation.

Case report: renal cell carcinoma presenting as hypertension in pregnancy.

Renal cell carcinoma is a rare, potentially fatal tumor that occasionally occurs during pregnancy. The probability of cure is directly related to the stage or degree of tumor dissemination. Surgical resection is the mainstay of treatment of this disease. A case of patient who was diagnosed with a renal mass in the second trimester of pregnancy is reported. She underwent left radical nephrectomy at 17 weeks' gestation.

Antithrombotic prophylaxis in multiparous women with preeclampsia or intrauterine growth retardation in an antecedent pregnancy.

OBJECTIVE: To determine whether prophylactic low dose aspirin (LDA) alone or in combination with low-molecular-weight-heparin (LMWH) reduces the recurrence of adverse pregnancy outcome (APO). STUDY DESIGN: In this retrospective cohort study, 84 consecutive multiparous patients with a previous history of severe preeclampsia (sPE) and intrauterine growth restriction (IUGR) (<10%ile) were assigned to receive no treatment, LDA alone, or LDA and LMWH. Odds ratios were calculated from logistic regression models. RESULTS: Combined LDA and LMWH significantly reduced the risk of developing IUGR in the index pregnancy (OR = 0.16, 95% CI: 0.03-0.98). Among women with antecedent sPE (n=52), combined treatment reduced APO in the index pregnancy (OR = 0.08, CI: 0.01-0.96), IUGR (OR = 0.02, CI: <0.01-0.46), and IUGR with sPE (OR = 0.08, CI: 0.01-0.96). CONCLUSION: Combined treatment with LDA and LMWH is strongly protective against the development of APO in a cohort of women with antecedent APO.

A prospective study of the role of ultrasound in the management of adnexal masses in pregnancy.

OBJECTIVE: To assess the clinical relevance of adnexal masses in pregnancy and the usefulness of ultrasound in their management. DESIGN: A prospective study on pregnancy complicated by adnexal masses. SETTING: Department of Obstetrics and Gynaecology in Italy. POPULATION: 6636 women with pregnancy in utero followed in our clinic from January 1996 to December 1999. METHODS: From 1996 to 1999, all ovarian cysts with a diameter exceeding 3 cm were prospectively recorded and followed. The management was expectant except in case of symptoms or suspected malignant features. Cysts suggestive of borderline tumours were treated expectantly. MAIN OUTCOME MEASURES: Clinical relevance of adnexal masses in pregnancy, the outcome of these pregnancies and the usefulness of ultrasound examination in their management. RESULTS: We detected 82 cysts in 79 of 6636 women (1.2 in 100 term pregnancies). Sixty-eight women were asymptomatic at the time of diagnosis, whereas 11 (13.9%) were diagnosed because of pain. Diagnosis occurred in the first trimester for 57 cases and in the second or third trimester in 22 (27.8%). One-half of the cysts were simple and anechoic at ultrasound. Fifty-seven had a diameter not exceeding 5 cm. Forty-two cyst resolved in pregnancy without treatment. Three cysts required surgery within few days (torsion). One woman required laparotomy at the 37th week of gestation, due to torsion. When one case of termination was excluded, 78 women delivered at term (66 vaginally, 12 by caesarean section). Nineteen women underwent surgery after pregnancy. We recorded three Stage Ia borderline tumours, accounting for 3/82 cysts (3.6%) and 3/30 persisting masses (10%). CONCLUSION: Ultrasound allows definition of ovarian cysts in pregnancy and this positively impacts on management. The incidence of cancer among persistent masses is lower than previously reported. Acute complications in stable cysts are extremely uncommon after the first trimester. An expectant management is successful in the majority of cases and should be considered more often. Routine removal of persistent cysts is not justified.