Which Came First,Tumor Cells or Macrophages?

Organ specific metastasis might be based on the specific interactions between chemokines expressed in premetastatic sites and their receptors on tumor cells. The ligand/receptor system in host defense mechanism pertinent to immune cells like macrophages is supposed to be hijacked by tumor cells. Ectopic expression of receptors in tumor cells enables bidirectional signaling between primary tumors and distant metastatic organs. VEGF and TNFa secreted from primary tumors signal through circulatory system to stimulate lung endothelial cells and macrophages to enhance production of S100A8 and A9 as well as MIP-1a, which in turn stimulate primary tumor cells as well as macrophages in bone marrow to migrate over to the lungs presumably via local chemokine gradient. Although it is beyond discussion to determine which came first, tumor cells or macrophages, the bidirectional signals could amplify the migration of both cells to accomplish metastasis.     

Breast Tumor Heterogeneity: Cancer Stem Cells or Clonal Evolution?

Breast tumors are composed of a variety of cell types with distinct morphologies and behaviors. It is not clear how this tumor heterogeneity comes about. Two popular concepts that attempt to explain this are the cancer stem cell hypothesis and the clonal evolution model. Each of these ideas has been investigated for some time, leading to the accumulation of numerous findings that are used to support one or the other. Although the two views share some similarities, they are fundamentally different notions with very different clinical implications. Analysis of the research backing each concept, along with a review of the results of our recent study investigating putative breast cancer stem cells, suggests how the cancer stem cell hypothesis and the clonal evolution model may be involved in generating breast tumor heterogeneity. An understanding of this process will allow the development of more effective ways to treat and prevent breast cancer.     

Tumor Associated Macrophages Protect Colon Cancer Cells from TRAIL-Induced Apoptosis through IL-1β- Dependent Stabilization of Snail in Tumor Cells

Background

We recently reported that colon tumor cells stimulate macrophages to release IL-1β, which in turn inactivates GSK3β and enhances Wnt signaling in colon cancer cells, generating a self-amplifying loop that promotes the growth of tumor cells.

Principal Findings

Here we describe that macrophages protect HCT116 and Hke-3 colon cancer cells from TRAIL-induced apoptosis. Inactivation of IL-1β by neutralizing IL-1β antibody, or silencing of IL-1β in macrophages inhibited their ability to counter TRAIL-induced apoptosis. Accordingly, IL-1β was sufficient to inhibit TRAIL-induced apoptosis. TRAIL-induced collapse of the mitochondrial membrane potential (Δψ) and activation of caspases were prevented by macrophages or by recombinant IL-1β. Pharmacological inhibition of IL-1β release from macrophages by vitamin D₃, a potent chemopreventive agent for colorectal cancer, restored the ability of TRAIL to induce apoptosis of tumor cells cultured with macrophages. Macrophages and IL-1β failed to inhibit TRAIL-induced apoptosis in HCT116 cells expressing dnIκB, dnAKT or dnTCF4, confirming that they oppose TRAIL-induced cell death through induction of Wnt signaling in tumor cells. We showed that macrophages and IL-1β stabilized Snail in tumor cells in an NF-κB/Wnt dependent manner and that Snail deficient tumor cells were not protected from TRAIL-induced apoptosis by macrophages or by IL-1β, demonstrating a crucial role of Snail in the resistance of tumor cells to TRAIL.

Significance

We have identified a positive feedback loop between tumor cells and macrophages that propagates the growth and promotes the survival of colon cancer cells: tumor cells stimulate macrophages to secrete IL-1β, which in turn, promotes Wnt signaling and stabilizes Snail in tumor cells, conferring resistance to TRAIL. Vitamin D₃ halts this amplifying loop by interfering with the release of IL-1β from macrophages. Accordingly, vitamin D₃ sensitizes tumor cells to TRAIL-induced apoptosis, suggesting that the therapeutic efficacy of TRAIL could be augmented by this readily available chemopreventive agent.     

Passive Glial Cells, Fact or Artifact?

Astrocytes that are recorded in acute tissue slices of rat hippocampus using whole-cell patch-clamp, commonly exhibit voltage-activated Na⁺ and K⁺ currents. Some reports have described astrocytes that appear to lack voltage-activated currents and proposed that these cells constitute a subpopulation of electrophysiologically passive astrocytes. We show here that these cells can spontaneously change during a recording unmasking expression of previously suppressed voltage-activated currents, suggesting that such cells do not represent a subpopulation of passive astrocytes. Superfusion of a low Ca²⁺/EGTA solution was able to reversibly suppress voltage-activated K⁺ currents in cultured astrocytes. Currents were restored upon addition of normal bath Ca²⁺. These effects of Ca²⁺ on both outward and inward K⁺ currents were dose- and time-dependent, with increasing concentrations of Ca²⁺ (from 0 to 800 μm) leading to a gradual unmasking of voltage-dependent outward and inward K⁺ currents. The transition from an apparently passive cell to one exhibiting prominent voltage-activated currents was not associated with any changes in membrane capacitance or access resistance. By contrast, in cells in which low access resistance or poor seal accounted for the absence of voltage-activated currents, improvement of cell access was always accompanied by changes in series resistance and membrane capacitance. We propose that spillage of pipette solution containing low Ca²⁺/EGTA during cell approach in slice recordings and/or poor cell access, lead to a transient masking of voltage-activated currents even in astrocytes that express prominent voltage-activated currents. These cells, however, do not constitute a subpopulation of electrophysiologically passive astrocytes. Received: 22 April 1998/Revised: 8 September 1998     

How Does Brazilian Green Propolis Act in Normal and Tumor Cells? Identification of Compounds in or out Monocytes or HEp-2 Cells

The aim of this study was to identify propolis compounds after incubation of normal and tumor cells (monocytes and HEp-2 cells, respectively) with Brazilian green propolis, in the lysate and supernatant of cell cultures and within these cells by gas chromatography-mass spectrometry (GC/MS). Cinnamic acid derivatives were generally localized in the lysate of both cell lines after incubation, suggesting these compounds are actively transported across the membrane into the cytoplasm. Terpenes were also found in the lysate. Artepillin C, in contrast, was localised only in the supernatant. Some constituents were unobservable after incubation, especially in monocytes, suggesting the compounds had been degraded. Our findings shed light on the possible sites of action (intracellular or via a cell membrane protein) and the bioavailability of various constituents of propolis, as well as possible modes of delivery of bioactive constituents.     

Which came first, the lung or the breath?

Lungs are the characteristic air-filled organs (AO) of the Polypteriformes, lungfish and tetrapods, whereas the swimbladder is ancestral in all other bony fish. Lungs are paired ventral derivatives of the pharynx posterior to the gills. Their respiratory blood supply is the sixth branchial artery and the venous outflow enters the heart separately from systemic and portal blood at the sinus venosus (Polypteriformes) or the atrium (lungfish), or is delivered to a separate left atrium (tetrapods). The swimbladder, on the other hand, is unpaired, and arises dorsally from the posterior pharynx. It is employed in breathing in Ginglymodi (gars), Halecomorphi (bowfin) and in basal teleosts. In most cases, its respiratory blood supply is homologous to that of the lung, but the vein drains to the cardinal veins. Separate intercardiac channels for oxygenated and deoxygenated blood are lacking. The question of the homology of lungs and swimbladders and of breathing mechanisms remains open. On the whole, air ventilatory mechanisms in the actinopterygian lineage are similar among different groups, including Polypteriformes, but are distinct from those of lungfish and tetrapods. However, there is extreme variation within this apparent dichotomy. Furthermore, the possible separate origin of air breathing in actinopterygian and 'sarcopterygian' lines is in conflict with the postulated much more ancient origin of vertebrate air-breathing organs. New studies on the isolated brainstem preparation of the gar (Lepisosteus osseus) show a pattern of efferent activity associated with a glottal opening that is remarkably similar to that seen in the in-vitro brainstem preparation of frogs and tadpoles. Given the complete lack of evidence for AO in chondrichthyans, and the isolated position of placoderms for which buoyancy organs of uncertain homology have been demonstrated, it is likely that homologous pharyngeal AO arose in the ancestors of early bony fish, and was pre-dated by behavioral mechanisms for surface (water) breathing. The primitive AO may have been the posterior gill pouches or even the modified gills themselves, served by the sixth branchial artery. Further development of the dorsal part may have led to the respiratory swimbladder, whereas the paired ventral parts evolved into lungs.     

Which came first,the virus or the cell?

The nature of viruses and the fundamental difference between their reproduction mechanism and cell division are discussed. The ways for storage and expression of genetic information in viruses are considerably more diverse than in cells. It is widely accepted nowadays that the “RNA world” appeared earlier than the “DNA world.” Hypotheses of the origin of viruses are discussed in conjunction with these theories (a hypothesis that cells with a RNA-genome appeared first, and were followed by viruses, and a hypothesis according to which RNA-containing viruses appeared first). It is suggested in both cases that the DNA-genomes first appeared in viruses, and that viruses played a definitive role in the origin of archaeans, eubacteria, and eukaryotes.     

Tumor counterattack: fact or fiction?

Cancer development relies on a variety of mechanisms that facilitate tumor growth despite the presence of a functioning immune system. Understanding these mechanisms may foster novel therapeutic approaches for oncology and organ transplantation. By expression of the apoptosis-inducing protein CD95L (FasL, APO-1L, CD178), tumors may eliminate tumor-infiltrating lymphocytes and suppress anti-tumor immune responses, a phenomenon called tumor counterattack. On the one hand, preliminary evidence of tumor counterattack in human tumors exists, and CD95L expression can prevent T-cell responses in vitro. On the other hand, CD95L-expressing tumors are rapidly rejected and induce inflammation in mice. Here, we summarize and discuss the consequences of CD95L expression of tumor cells and its contribution to immune escape.This article is a symposium paper from the conference Tumor Escape and Its Determinants, held in Salzburg, Austria, on 10–13 October 2004.     

Macrophages in CNS Remyelination: Friend or Foe?

Hematogenous macrophages and resident brain microglia are agents of demyelination in multiple sclerosis (MS) and paradoxically may also participate in remyelination. In vitro studies have shown that macrophage enrichment of aggregate brain cultures promotes myelination per se and enhances the capacity to remyelinate following a demyelinating episode. It has been hypothesized that remyelination in MS is implemented by surviving dedifferentiated oligodendrocytes or by newly recruited progenitors that migrate, proliferate and synthesize myelin in response to signalling molecules in the local environment. We postulate that macrophage-derived cytokines or growth factors may directly or indirectly promote oligodendroglial proliferation and differentiation, contributing to myelin repair in inflammatory demyelinating disease.