On the origin of cancer metastasis.

Metastasis involves the spread of cancer cells from the primary tumor to surrounding tissues and to distant organs and is the primary cause of cancer morbidity and mortality. In order to complete the metastatic cascade, cancer cells must detach from the primary tumor, intravasate into the circulatory and lymphatic systems, evade immune attack, extravasate at distant capillary beds, and invade and proliferate in distant organs. Currently, several hypotheses have been advanced to explain the origin of cancer metastasis.

HIV-1 Nef in macrophage-mediated disease pathogenesis.

Combined anti-retroviral therapy (cART) has significantly reduced the number of AIDS-associated illnesses and changed the course of HIV-1 disease in developed countries. Despite the ability of cART to maintain high CD4+ T-cell counts, a number of macrophage-mediated diseases can still occur in HIV-infected subjects. These diseases include lymphoma, metabolic diseases, and HIV-associated neurological disorders.

Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer?

Malignant brain cancer persists as a major disease of morbidity and mortality. The failure to recognize brain cancer as a disease of energy metabolism has contributed in large part to the failure in management. As long as brain tumor cells have access to glucose and glutamine, the disease will progress.

Hypothesis: are neoplastic macrophages/microglia present in glioblastoma multiforme?

Most malignant brain tumours contain various numbers of cells with characteristics of activated or dysmorphic macrophages/microglia. These cells are generally considered part of the tumour stroma and are often described as TAM (tumour-associated macrophages). These types of cells are thought to either enhance or inhibit brain tumour progression.

HIV-1 nef protein visits B-cells via macrophage nanotubes: a mechanism for AIDS-related lymphoma pathogenesis?

This letter refers to the recent demonstration that HIV-1 infected macrophages form specialized conduits that connect to B-cells (1). The conduit selectively transports the HIV-1 nef protein, providing nef with numerous means to interfere with cellular processes. Currently, no consideration of the connection between the conduit and the development of AIDS-related lymphoma (ARL) has been offered.

HIV-1 phylogenetic analysis shows HIV-1 transits through the meninges to brain and peripheral tissues.

Brain infection by the human immunodeficiency virus type 1 (HIV-1) has been investigated in many reports with a variety of conclusions concerning the time of entry and degree of viral compartmentalization. To address these diverse findings, we sequenced HIV-1 gp120 clones from a wide range of brain, peripheral and meningeal tissues from five patients who died from several HIV-1 associated disease pathologies. High-resolution phylogenetic analysis confirmed previous studies that showed a significant degree of compartmentalization in brain and peripheral tissue subpopulations.

Perspectives on the mesenchymal origin of metastatic cancer.

Emerging evidence suggests that many metastatic cancers arise from cells of the myeloid/macrophage lineage regardless of the primary tissue of origin. A myeloid origin of metastatic cancer stands apart from origins involving clonal evolution or epithelial-mesenchymal transitions. Evidence is reviewed demonstrating that numerous human cancers express multiple properties of macrophages including phagocytosis, fusogenicity, and gene/protein expression.

Metabolic management of brain cancer.

Malignant brain tumors are a significant health problem in children and adults. Conventional therapeutic approaches have been largely unsuccessful in providing long-term management. As primarily a metabolic disease, malignant brain cancer can be managed through changes in metabolic environment.

Calorie restriction as an anti-invasive therapy for malignant brain cancer in the VM mouse.

GBM (glioblastoma multiforme) is the most aggressive and invasive form of primary human brain cancer. We recently developed a novel brain cancer model in the inbred VM mouse strain that shares several characteristics with human GBM. Using bioluminescence imaging, we tested the efficacy of CR (calorie restriction) for its ability to reduce tumour size and invasion.

Glutamine targeting inhibits systemic metastasis in the VM-M3 murine tumor model.

Metastatic cancer is a major cause of morbidity and mortality. Current therapeutic options consist of chemotherapy, radiation or targeted therapies. However, these therapies are often toxic, effective over a small range of cancer types or result in drug resistance.

The role of macrophages in the development and progression of AIDS-related non-Hodgkin lymphoma.

Despite HAART, patients infected with HIV develop NHL at a significantly higher level than the noninfected population. The primary difference between lymphoma in non-HIV-infected individuals and those with ARL is that ARL is consistently high-grade and metastatic. The emergence of ARL is associated with the presence of macrophage viral reservoirs, similar to what has been observed for HAD.

Distinct patterns of HIV-1 evolution within metastatic tissues in patients with non-Hodgkins lymphoma.

Despite highly active antiretroviral therapy (HAART), AIDS related lymphoma (ARL) occurs at a significantly higher rate in patients infected with the Human Immunodeficiency Virus (HIV) than in the general population. HIV-infected macrophages are a known viral reservoir and have been shown to have lymphomagenic potential in SCID mice; therefore, there is an interest in determining if a viral component to lymphomagenesis also exists. We sequenced HIV-1 envelope gp120 clones obtained post mortem from several tumor and non-tumor tissues of two patients who died with AIDS-related Non-Hodgkin's lymphoma (ARL-NH).

Influence of methotrexate and cisplatin on tumor progression and survival in the VM mouse model of systemic metastatic cancer.

We recently identified a new tumor (VM-M3), which arose spontaneously in the brain of an inbred VM mouse. When grown outside the brain, the VM-M3 tumor expresses all major biological processes of metastasis to include local invasion, intravasation, immune system survival, extravasation, and secondary tumor formation involving lung, liver, kidney, spleen and brain. The VM-M3 tumor also expresses multiple properties of macrophage-like cells similar to those described previously in numerous human metastatic cancers suggesting that the VM-M3 model will be useful for studying most types of metastatic cancer, regardless of tissue origin.

Metastatic cancer cells with macrophage properties: evidence from a new murine tumor model.

Metastasis is the process by which cancer cells disseminate from the primary neoplasm and invade surrounding tissue and distant organs, and is the primary cause of morbidity and mortality for cancer patients. Most conventional cancer therapies are ineffective in managing tumor metastasis. This has been due in large part to the absence of in vivo metastatic models that represent the full spectrum of metastatic disease.

Up-regulation of NG2 proteoglycan and interferon-induced transmembrane proteins 1 and 3 in mouse astrocytoma: a membrane proteomics approach.

Although brain tumors are classified as if their lineage were well understood, the relationship between the molecular events that specify neural cell lineage and brain tumors remains enigmatic. Traditionally, cell surface membrane antigens have served as biomarkers that distinguish brain tumor origin and malignancy. In this study, membrane proteins were identified from a terminally differentiated mouse astrocyte (AC) and CT-2A astrocytoma (CT-2A) cell line using liquid-chromatography coupled with tandem mass spectrometry (LC-MS/MS).

Differentiating N-linked glycan structural isomers in metastatic and nonmetastatic tumor cells using sequential mass spectrometry.

In an effort to understand the role of molecular glycosylation in cancer a murine model has been used to characterize and fingerprint malignancies in established cell lines that manifest all the hallmarks of metastatic disease: spontaneous development, local invasion, intravasation, immune system survival, extravasation, and secondary tumor formation involving liver, kidney, spleen, lung, and brain. Using astrocyte cell controls, we compared N-linked glycosylation from a nonmetastatic brain tumor cell line and two different metastatic brain tumor cells. Selected ions in each profile were disassembled by ion trap mass spectrometry (MS(n)) which exhibited multiple structural differences between each tissue.