Odile David

Blockade of B7-H1 improves myeloid dendritic cell–mediated antitumor immunity

Suppression of dendritic cell function in cancer patients is thought to contribute to the inhibition of immune responses and disease progression. Molecular mechanisms of this suppression remain elusive, however. Here, we show that a fraction of blood monocyte-derived myeloid dendritic cells (MDCs) express B7-H1, a member of the B7 family, on the cell surface. B7-H1 could be further upregulated by tumor environmental factors. Consistent with this finding, virtually all MDCs isolated from the tissues or draining lymph nodes of ovarian carcinomas express B7-H1. Blockade of B7-H1 enhanced MDC-mediated T-cell activation and was accompanied by downregulation of T-cell interleukin (IL)-10 and upregulation of IL-2 and interferon (IFN)-γ. T cells conditioned with the B7-H1–blocked MDCs had a more potent ability to inhibit autologous human ovarian carcinoma growth in non-obese diabetic–severe combined immunodeficient (NOD-SCID) mice. Therefore, upregulation of B7-H1 on MDCs in the tumor microenvironment downregulates T-cell immunity. Blockade of B7-H1 represents one approach for cancer immunotherapy.

Bone Marrow Is a Reservoir for CD4+CD25+ Regulatory T Cells that Traffic through CXCL12/CXCR4 Signals

CD4+CD25+ regulatory T cells (Tregs) mediate peripheral T-cell homeostasis and contribute to self-tolerance. Their homeostatic and pathologic trafficking is poorly understood. Under homeostatic conditions, we show a relatively high prevalence of functional Tregs in human bone marrow. Bone marrow strongly expresses functional stromal-derived factor (CXCL12), the ligand for CXCR4. Human Tregs traffic to and are retained in bone marrow through CXCR4/CXCL12 signals as shown in chimeric nonobese diabetic/severe combined immunodeficient mice. Granulocyte colony-stimulating factor (G-CSF) reduces human bone marrow CXCL12 expression in vivo, associated with mobilization of marrow Tregs to peripheral blood in human volunteers. These findings show a mechanism for homeostatic Treg trafficking and indicate that bone marrow is a significant reservoir for Tregs. These data also suggest a novel mechanism explaining reduced acute graft-versus-host disease and improvement in autoimmune diseases following G-CSF treatment.

Phospho-Akt Overexpression in Non–Small Cell Lung Cancer Confers Significant Stage-Independent Survival Disadvantage

Purpose: Akt is a signal transduction protein that plays a central role in inhibiting apoptosis in a variety of cell types including human cancer cells. In cell lines derived from human non–small cell lung cancers (NSCLCs), Akt has been shown to confer chemoresistance by inhibition of apoptosis in response to different chemotherapeutic agents including platinum-based agents, which are often the first-line therapy for NSCLCs. Only 20% to 30% of patients with NSCLC treated with chemotherapy have clinical evidence of response. The purpose of this study is to determine whether or not overexpression of activated Akt [i.e., phosphorylated Akt (pAkt)] is correlated with survival. Experimental Design: We studied tumors from 61 patients with NSCLC in three tissue microarrays. All patients were followed for a period of 10 years or until death. The arrays were studied immunohistochemically with antibodies against pAkt, p53, and Ki-67. Results: There was a statistically significant difference in survival between the 14 patients with strong pAkt staining and the 47 patients with weak to absent pAkt staining both by log-rank (P = 0.0416) and Breslow analysis (P = 0.0446). Difference in survival time with respect to pAkt status was also statistically significant even after accounting for stage at diagnosis (P = 0.004). Neither p53 nor Ki-67 was a statistically significant prognostic factor. Conclusions: Overexpression of pAkt is an independent prognostic factor. Additional studies of human NSCLCs are warranted to drive the development of targeted tumor-specific antineoplastic therapies.

Blood histamine is associated with coronary artery disease, cardiac events and severity of inflammation and atherosclerosis

Background: Mast cells are prevalent in the shoulder of unstable atheromas; cardiac mast cells secrete proteases capable of activating matrix metalloproteinases. Histamine is essential in the inflammatory cascade of the unstable plaque. Ascorbate depletion has been correlated with histaminemia which has been shown to impair endothelial‐dependent vasodilation. This study evaluates whether oxidative stress as measured by isoprostanes (PGF2α) coupled with an inflammatory state characterized by histaminemia predisposes patients to acute coronary syndrome (ACS).

Predisposition to atypical teratoid/rhabdoid tumor due to an inherited INI1 mutation.

Germline mutations of the INI1 gene predispose children to the development of rhabdoid tumors. Reports of familial cases, however, are extremely rare.

Multifocal granular cell tumor of the esophagus and proximal stomach with infiltrative pattern: A case report and review of the literature

The granular cell tumor is a solitary painless nodule that arises most commonly on the skin or the tongue. The vast majority are benign. Approximately 5% to 9% of granular cell tumors have been reported in the gastrointestinal tract, most commonly in the esophagus. We report a case of a 45-year-old African American woman with multifocal granular cell tumors of the esophagus and proximal stomach. Two lesions within the distal esophagus and proximal stomach were characteristic nodular granular cell tumors. Within the mid esophagus there was poorly defined transmural involvement by benign-appearing granular cells. This pattern of infiltration by benign cells is uncharacteristic. A review of the literature with emphasis on the determination of malignancy is also presented.

MEK5/ERK5 Signaling Suppresses Estrogen Receptor Expression and Promotes Hormone-Independent Tumorigenesis

Endocrine resistance and metastatic progression are primary causes of treatment failure in breast cancer. While mitogen activated protein kinases (MAPKs) are known to promote ligand-independent cell growth, the role of the MEK5-ERK5 pathway in the progression of clinical breast carcinoma remains poorly understood. Here, we demonstrated increased ERK5 activation in 30 of 39 (76.9%) clinical tumor samples, as well as across breast cancer cell systems. Overexpression of MEK5 in MCF-7 cells promoted both hormone-dependent and hormone-independent tumorigenesis in vitro and in vivo and conferred endocrine therapy resistance to previously sensitive breast cancer cells. Expression of MEK5 suppressed estrogen receptor (ER)α, but not ER-β protein levels, and abrogated downstream estrogen response element (ERE) transcriptional activity and ER-mediated gene transcription. Global gene expression changes associated with upregulation of MEK5 included increased activation of ER-α independent growth signaling pathways and promotion of epithelial-to-mesenchymal transition (EMT) markers. Taken together, our findings show that the MEK5-ERK5 pathway mediates progression to an ER(−), mesenchymal and endocrine therapy resistant phenotype. Given the need for new clinical therapeutic targets, our results demonstrate the therapeutic potential of targeting the MEK5-ERK5 pathway in breast cancer.

Akt and PTEN: new diagnostic markers of non-small cell lung cancer?

We are particularly interested in testing the principles of cell proliferation and apoptosis in the microenvironment of human lung cancers with respect to the cell survival protein Akt1 and PTEN2. Akt is a cytosolic protein which promotes cell survival by phosphorylative inactivation of targets in apoptotic pathways. Akt has been found to play a role in the survival of experimental cancer cell lines in breast, prostate, ovary, lung and brain tissue. PTEN is a tumor suppressor gene whose protein product is expressed in inverse proportion to phosphorylated Akt in endometrial and breast cancer cell lines. No studies of the diagnostic significance of Akt and PTEN in human lung cancers have been reported.

Self-stenting with a crack pipe: The ultimate in 'managed care'

Accessible online at: www.karger.com/res Fig. 1. Posterior-anterior chest radiograph showing a cylindrical object in the left mainstem bronchus. Fig. 2. Computerized tomography of the chest showing a radioopaque hollow object in the left mainstem bronchus. Fig. 3. ‘Crack pipe’ fragments after removal. A 30-year-old man presented to the emergency department with hemoptysis. He was a habitual ‘crack-cocaine’ user and had last smoked 1 week prior. He had no other complaints. He was treated with oral antibiotics for presumed bronchitis and discharged home. Two weeks later he again presented with hemoptysis. Chest radiography and computed tomography (fig. 1, 2) at that time revealed a cylindrical density in the lumen of the left mainstem bronchus resembling a stent. The patient had no recall of stenting. Bronchoscopy revealed a 1-cm diameter glass tube with jagged edges facing proximally that was removed from the left mainstem bronchus by rigid bronchoscopy (fig. 3). Following a 10-day course of oral steroids and antibiotics, repeat bronchoscopy revealed a normal left mainstem bronchus. Interestingly, the patient had no recollection of aspiration and denied having broken his crack pipe. ‘Crack-cocaine’ is the free-base of cocaine hydrochloride formed by boiling a mixture of cocaine, baking soda and water. ‘Crack-cocaine’ is heat stable allowing it to be smoked, often through a glass pipe. Smoking is desirable to the user because it provides an onset of action that is quicker than either nasal inhalation or intravenous injection. It is estimated that 6% of habitual ‘crack-cocaine’ smokers report at least occasional hemoptysis following use [1]. Hemoptysis associated with ‘crack-cocaine’ use may be the result of diffuse alveolar hemorrhage induced by vasoconstriction or direct toxicity of cocaine, cocaine induced rhabdomyolysis, pulmonary infarction, cocaine-induced thrombocytopenia [2], or foreign body as in this case. The syndrome of crack lung may include pulmonary hemorrhage in combination with chest pain, pulmonary edema, and an interstitial lung process.

Immunohistochemical analysis of differentiation in static and mixed prostate cancer spheroids

Neoplastic multicellular spheroids are in vitro models of solid tumors employed in drug testing and basic research. This study compares differentiation in static and mixed prostate cancer spheroids. Staining intensity of prostate specific antigen (PSA) was down‐regulated upon mixing from 0.21 ± 0.03 to 0.13 ± 0.03 in LNCaP multicellular spheroids, and from 0.13 ± 0.04 to 0.03 ± 0.02 in DU 145 multicellular spheroids. This was accompanied by 65% increase in the expression of cytokeratins 8 and 18 in DU 145 spheroids. PSA expression extended 60 μm within static spheroids and was disrupted in mixed culture. Diminished PSA expression and spatial organization suggests a more aggressive cancer. Higher cytokeratin expression could result from either differentiation towards a luminal phenotype or activation of the Ras pathway during dedifferentiation. THus, the existing paradigm of differentiation established for normal tissue does not apply for our neoplastic spheroids. Cell dedifferentiation is attributed to improved interstitial transport and synthesis of extracellular matrix.