The Pentose Phosphate Pathway Dynamics in Cancer and Its Dependency on Intracellular pH.

The Pentose Phosphate Pathway (PPP) is one of the key metabolic pathways occurring in living cells to produce energy and maintain cellular homeostasis. Cancer cells have higher cytoplasmic utilization of glucose (glycolysis), even in the presence of oxygen; this is known as the "Warburg Effect". However, cytoplasmic glucose utilization can also occur in cancer through the PPP.

The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer.

Cancer cells and tissues have an aberrant regulation of hydrogen ion dynamics driven by a combination of poor vascular perfusion, regional hypoxia, and increased the flux of carbons through fermentative glycolysis. This leads to extracellular acidosis and intracellular alkalinization. Dysregulated pH dynamics influence cancer cell biology, from cell transformation and tumorigenesis to proliferation, local growth, invasion, and metastasis.

Mitochondrial Toxicity of Azithromycin Results in Aerobic Glycolysis and DNA Damage of Human Mammary Epithelia and Fibroblasts.

Mitochondria evolved from free-living bacteria via endocytosis within eukaryotic host cells millions of year ago. We hypothesized that antibiotics cause mammalian mitochondrial damage while causing bacterial lethality. Mitochondrial toxicity of azithromycin in human mammary epithelia MCF-12A and fibroblasts were tested by fluorescent and transmission electron microscopy.

The Role of Sodium Hydrogen Exchanger 1 in Dysregulation of Proton Dynamics and Reprogramming of Cancer Metabolism as a Sequela.

Cancer cells have an unusual regulation of hydrogen ion dynamics that are driven by poor vascularity perfusion, regional hypoxia, and increased glycolysis. All these forces synergize/orchestrate together to create extracellular acidity and intracellular alkalinity. Precisely, they lead to extracellular pH (pH) values as low as 6.

The adverse effect of gentamicin on cell metabolism in three cultured mammary cell lines: "Are cell culture data skewed?".

Many cells are cultured in media that contains an antibiotic to prevent bacterial contamination. Mycoplasma and other bacterial contamination is a serious problem for those involved in cell culture. Antibiotics in the media helps prevent this contamination and make life easier for the investigators; as performing cell culture experiments in antibiotic free media is difficult and requires vigorous sterile technique.

Decreased Iron in Cancer Cells and Their Microenvironment Improves Cytolysis of Breast Cancer Cells by Natural Killer Cells.

The association of iron with anticancer immunity is unclear. In order to determine the role of iron in anticancer immunity, we manipulated intracellular iron levels of the human MCF-7 and MDA-MB-231 breast cancer cell lines, and measured cytolysis of breast cancer cells by the natural killer cell line NK-92MI, nitric oxide (NO) production, tumor necrosis factor alpha (TNFα) production and gene expression of ferritin heavy chain (FTH1). We found that NK-92MI increased synthesis and release of NO and TNFα into the medium during co-culturing of NK-92MI cells with MCF-7 or MDA-MB-231 cells.

Exogenous normal mammary epithelial mitochondria suppress glycolytic metabolism and glucose uptake of human breast cancer cells.

We hypothesized that normal mitochondria inhibited cancer cell proliferation and increased drug sensitivity by the mechanism of suppression of cancer aerobic glycolysis. To demonstrate the mechanism, we used real-time PCR and glycolysis cell-based assay to measure gene expression of glycolytic enzymes and glucose transporters, and extracellular lactate production of human breast cancer cells. We found that isolated fluorescent probe-stained mitochondria of MCF-12A (human mammary epithelia) could enter into human breast cancer cell lines MCF-7, T47D, and MDA-MB-231, confirmed by fluorescent and confocal microscopy.

Adjuvant breast cancer vaccine improves disease specific survival of breast cancer patients with depressed lymphocyte immunity.

Purpose: Beginning in 1995 breast cancer patients were vaccinated in the adjuvant setting with an autologous, allogeneic whole cell vaccine to evaluate the effect on host lymphocyte immunity and disease specific survival.

Methods: The breast cancer patients had host lymphocyte immunity against tumor associated antigens evaluated by a Lymphocyte Blastogenesis Assay (LBA) before vaccination. Thirty-seven patients with depressed immunity were vaccinated in the adjuvant setting.

Progranulin (GP88) tumor tissue expression is associated with increased risk of recurrence in breast cancer patients diagnosed with estrogen receptor positive invasive ductal carcinoma.

Introduction: GP88 (progranulin) has been implicated in tumorigenesis and resistance to anti-estrogen therapies for estrogen receptor positive (ER+) breast cancer. Previous pathological studies showed that GP88 is expressed in invasive ductal carcinoma (IDC), but not in normal mammary epithelial tissue, benign lesions or lobular carcinoma. Based on these results, the present study examines GP88 prognostic significance in association with recurrence and death risks for ER+ IDC patients.

Down-regulation of expression of interleukin-6 and its receptor results in growth inhibition of MCF-7 breast cancer cells.

Interleukin-6 (IL-6) plays an important role in the neoplastic process through its action on cancer cell adhesion, motility, proliferation, tumor-specific antigen expression, and thrombopoiesis. IL-6 exerts its activity by binding to a high affinity receptor complex consisting of two membrane glycoproteins: the 80 kDa IL-6 a-receptor subunit (IL-6R) and the 130 kDa signal-transducing protein (GP130). In the present study, MCF-7 breast cancer cells were cultured with human IL-6 and IL-6 soluble receptor (sIL-6R).

Human leukocyte antigen G expression in breast cancer: role in immunosuppression.

Human leukocyte antigen G (HLA-G) is an immunotolerant nonclassical major histocompatibility complex Class Ib molecule. It is expressed by trophoblastic placental cells during pregnancy to protect the fetus from maternal alloreactivity. HLA-G is overexpressed in tumors and involved in cancer immune evasion.

Manipulation of iron transporter genes results in the suppression of human and mouse mammary adenocarcinomas.

Since malignant cells often have a high demand for iron, we hypothesize that breast cancer cells may alter the expression of iron transporter genes including iron importers [transferrin receptor (TFRC) and solute carrier family 11 (proton-coupled divalent metal ion transporters), member 2 (SLC11A2)] and the iron exporter SLC40A1 (ferroportin), and additionally that the growth of breast cancer can be inhibited by manipulating iron transporter gene expression. To test our hypothesis, reverse transcription polymerase chain reaction (RT-PCR) was used to determine mRNA expression of iron transporter genes in normal human mammary epithelial MCF-12A cells and human breast cancer MCF-7 cells. Antisense oligonucleotides were employed to suppress the expression of TFRC gene in the 4T1 mammary adenocarcinoma in both cell culture and a mouse tumor model.

Stereotactic radiofrequency ablation: a minimally invasive technique for nonpalpable breast cancer in postmenopausal patients.

Background: The purpose of this study was to determine the feasibility of radiofrequency ablation (RFA) of nonpalpable breast cancer in postmenopausal women, and report on long-term follow-up with clinical examination and mammography.

Methods: Since November 2000, we have performed RFA on stereotactically localized nonpalpable breast cancers (only mammographic densities) in women older than 65 years with other serious health problems.

Results: The first patient had the procedure done in the office with sedation and local anesthesia.

Complete resolution of malignant ascites in stage IV breast cancer by peritoneal drainage and innovative chemoimmunotherapy: a case report.

Malignant ascites is a very serious and difficult to manage problem in the cancer patient. It is a sign of late stage disease and treatment is mainly palliative. Therefore the treatment should produce minimal discomfort and have few side effects.

Induction of apoptosis by iron depletion in the human breast cancer MCF-7 cell line and the 13762NF rat mammary adenocarcinoma in vivo.

It is known that the interruption of normal iron metabolism with chelators of iron, toxic metals, toxic metals bound to transferrin, or anti-transferrin receptor antibodies leads to significant inhibition of tumor cell growth in cell culture systems and animal models. In the present study, we found that iron depletion was produced by the iron chelator deferoxamine mesylate, the free toxic metals gallium or indium, and the toxic metals gallium or indium bound to transferrin in the MCF-7 human breast cancer cell line, and this induced the condensation and fragmentation of chromatin, and the formation of DNA fragments characteristic of apoptosis. The induction of apoptosis was quantitated with acridine orange and ethidium bromide staining of apoptotic cells, separation of fragmented DNA from radiolabeled cells, and in situ terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) assays.

Radiofrequency ablation of a stereotactically localized nonpalpable breast carcinoma.

A nonpalpable breast lesion was detected in a 71-year-old woman who had returned for her annual mammogram. Stereotactic core needle biopsy revealed an infiltrating ductal carcinoma. The patient agreed to stereotactic localization and radiofrequency ablation of the lesion followed after 4 weeks by open surgical biopsy.

Gene targets of antisense therapies in breast cancer.

Advances in molecular and cell biology have led to further understanding of the mechanisms of malignant growth and metastasis in human breast cancer cells. Initiation and progression of breast cancer results from mutations and the abnormal expression of many genes that control cellular proliferation, differentiation, invasion, metastasis and sensitivity to therapy (chemotherapy and radiation therapy). Inhibition of host immunity also plays a role in breast cancer progression.

Antisense ferritin oligonucleotides inhibit growth and induce apoptosis in human breast carcinoma cells.

Background: Ferritin is the major iron-storage protein which sequesters and detoxifies excess iron that is taken up by cells but is not utilized in normal metabolic processes. Human ferritin consists of various combinations of heavy (FerH, Mr 21,000) and light (FerL, Mr 19,000) chains and excess iron leads to an increase in the synthesis of both heavy and light chains.

Materials And Methods: In this study four pairs of antisense oligodeoxynucleotides (ODNs) were synthesized: FerH-A1 and FerL-A1 were complementary to the 24-base pair sequence overlapping the starting codons of the FerH and FerL genes, respectively, but the sequences of FerH-A2 and FerL-A2 only covered the coding sequences of the ferritin genes.