Role of the vascular component in growth of solid tumors: a historical review

Angiogenesis is a fundamental biological process by which new capillary blood vessels are formed. It is essential in many physiological conditions, such as embryonic development, ovulation and wound repair, and pathological ones, such as arthritis, diabetic retinopathy, and tumours. Solid tumours have angiogenesis capacity, and tumour growth and metastasis are angiogenesis-dependent. Neoplastic cell populations can grow to form a clinically evident tumour only if the host produces a vascular network sufficient to sustain tumour growth. Furthermore, the new blood vessels provide a gateway for tumour cells to enter the circulation and metastasize to distant sites. Tumour angiogenesis is essentially mediated by angiogenic molecules elaborated by tumour cells. We review here the most important literature on this topic and emphasize the crucial and paradigmatic role of this biological process and its relevance in a possible anti-angiogenic therapeutic approach to the treatment of solid tumours.     

Proton magnetic resonance spectroscopy in patients with glial tumors: a multicenter study

Budding yeast (Saccharomyces cerevisiae) Rap1p has been expressed in fission yeast (Schizosaccharomyces pombe) under the control of the regulatable fructose bisphosphatase (fbp) promoter. When the fbp promoter was derepressed, cells containing the complete RAP1 gene failed to show any significant growth, suggesting that Rap1p is toxic. A derivative of Rap1p that has a temperature-sensitive mutation in the DNA-binding domain was not toxic in cells grown at 37 degrees C, a temperature at which DNA binding by rap1p(ts) is severely inhibited. Removal of a short region downstream of the DNA-binding domain, including a region previously shown to be essential for Rap1p toxicity in budding yeast, also abolished the toxic effect. The toxic effect of Rap1p has therefore been conserved between two distantly related yeasts. In budding yeast, overexpression of Rap1p also caused changes to the lengths of the telomeric repeats. No effects on telomeres were detected in fission yeast.     

Parkinson's disease in populations of African origin: a review

Several studies have reported a lower prevalence of Parkinson's disease (PD) in populations of African origin than in populations of European origin, raising the possibility that the former are protected against PD. However, the confounding effects of low case ascertainment and high selective mortality on PD prevalence estimates in populations of African origin cannot be ruled out at this time. One hypothesis consistent with available data is that populations of African origin are vulnerable to vascular parkinsonism, which is associated with high mortality.     

Concomitant chemoradiotherapy and malignant glial tumors in the adult

The prognosis of adult patients with malignant gliomas remains poor despite advances in neurosurgery and radiotherapy. Even if chemotherapy has done little to improve on these results, except in the treatment of oligodendrogliomas, many authors have proposed to test the effect of radiotherapy by adding concomitant chemotherapy. Unfortunately, the analysis of these studies is difficult because all these protocols are different with a small number of patients. Furthermore, there are only a few studies evaluated in well controlled clinical trials with homogeneous patient population. Important factors such as tumor grade, patient age, and Karnofsky score, which have a strong influence on survival in malignant gliomas, are not clearly evaluated. Whatever, all these studies suggest that concomitant radio-chemotherapy seems not be promising in the treatment of malignant gliomas.     

Role of intermediate filaments in migration, invasion and metastasis

The expression of intermediate filament proteins is remarkably tissue-specific which suggests that the intermediate filament (IF) type(s) present in cells is somehow related to their biological function. However, in some cancers-particularly malignant melanoma and breast carcinoma, there is a strong indication that vimentin and keratin IFs are coexpressed, thus presenting as a dedifferentiated or interconverted (between epithelial and mesenchymal) phenotype. In this review, two in vitro models are presented which recapitulate the interconverted phenotype in human melanoma and breast carcinoma, and allow, for the first time, unique observations to be made with respect to the role of IFs in cancer progression. These studies have provided direct evidence linking overexpression of keratin IFs in human melanoma with increased migratory and invasive activity in vitro, which can be down-regulated by substituting dominant-negative keratin mutants. Overexpression of vimentin IFs in the breast carcinoma model leads to augmentation of motility and invasiveness in vitro, which can be transiently down-regulated by treatment with antisense oligonucleotides to vimentin. Additional experimental evidence suggests that the mechanism(s) responsible for the differential expression of metastatic properties associated with the interconverted phenotype rest(s) in the unique interaction, either direct or indirect, of IFs with specific integrins interacting with the extracellular matrix. In this review, we discuss the observations derived from the human melanoma and breast carcinoma models to address the hypothesis that the ability to coexpress vimentin and keratins confers a selective advantage to tumor cells in their interpretation of and response to signaling cues from the extracellular matrix. The ramifications of these observations are discussed with respect to the patholophysiology of the respective in situ tumors.     

Calcium signalling in glial cells

Glial cells respond to a variety of external stimuli such as neurotransmitters, hormones or even mechanical stress by generating complex changes in the cytoplasmic Ca2+ concentration. This Ca2+ signal is controlled by an interplay of different mechanisms including plasmalemmal and intracellular Ca2+ channels, Ca2+ transporters and cytoplasmic Ca2+ buffers. In astrocytes, the Ca2+ signal can travel as waves within the syncytium spreading via gap junctions which might be regarded as a possible means for interglial communication. Ca2+ signalling is also an important medium for neurone-glia interaction: neuronal activity can trigger Ca2+ signals in glial cells and, in turn, there is evidence that glial Ca2+ signals can elicit responses in neurones. While glial cells are not equipped with the proper channels to generate action potentials, Ca2+ signalling could be the instrument by which these cells integrate and propagate signals in the CNS.     

Presence and significance of oxytocin receptors in human neuroblastomas and glial tumors

The potential contribution of cell-cell interactions and extracellular factors to cytoarchitectonic abnormalities in the cerebellum of the reeler mutant mouse was investigated by forming chimeras between the reeler and normal animals. The strain origin of Purkinje cells, granule cells and Golgi epithelial cells was immunohistologically identified with a strain-specific antibody. We analyzed 16 overt coat color chimeras, 10 reeler <--> C3H and 6 reeler <--> Balb/c. Abnormal behavioral traits of reeler were rescued in all chimeras. However, cerebellar histology was more affected in reeler <--> C3H chimeras than in reeler <--> Balb/c. Purkinje cells from the normal genotype occupy ectopic positions, and reeler genotype cells are arranged appropriately in the same chimeric cerebellum. We also obtained histologically normal chimeras with a significantly high contribution of the reeler genotype in Purkinje cells, Golgi epithelial cells and granule cells. These results clearly indicate that the abnormal cell positioning and cytoarchitecture of neurons and glia in the reeler is caused by a deficiency of extracellular environments, but is not determined cell-autonomously. The present data on chimeric mice suggest that Reelin is one of the important extracellular environmental factors that affects indirectly radial glial cells during cerebellar histogenesis.     

Contractile filaments in cells of regenerating tendon

An extensive cytoplasmic fibrillar system has been observed in fibroblast-like cell of regenerating tendon. It consists of bundles of actin filaments, which often show a cross-striated appearance due to electron dense bodies occurring throughout their length. The functional role of this contractile apparatus seems to be related to the process of movement and orientation of the newly formed cells and to the retraction of the regenerating tendon.     

The induction of lipid peroxidation in human brain glial tumors

Tissue examinations of glial tumors in the human brain revealed that therein lipid peroxidation could be induced by using bivalent iron salts, which is indicated by higher malonic dialdehyde levels. The authors have demonstrated that the glioma tissue levels of iron were statistically lower than those in the brain tissue. The induction in tumor tissue does not depend upon the degree of its malignancy, but it significantly differs from this parameter in the rabbit brain tissue. The induction of lipid peroxidation processes is accompanied by a lower cumulative antioxidative activity. The findings open new prospects for affecting tumor growth.     

Calcium waves in retinal glial cells

Calcium signals were recorded from glial cells in acutely isolated rat retina to determine whether Ca2+ waves occur in glial cells of intact central nervous system tissue. Chemical (adenosine triphosphate), electrical, and mechanical stimulation of astrocytes initiated increases in the intracellular concentration of Ca2+ that propagated at approximately 23 micrometers per second through astrocytes and Müller cells as intercellular waves. The Ca2+ waves persisted in the absence of extracellular Ca2+ but were largely abolished by thapsigargin and intracellular heparin, indicating that Ca2+ was released from intracellular stores. The waves did not evoke changes in cell membrane potential but traveled synchronously in astrocytes and Müller cells, suggesting a functional linkage between these two types of glial cells. Such glial Ca2+ waves may constitute an extraneuronal signaling pathway in the central nervous system.     

Role of calcium oxalate monohydrate crystal interactions with renal epithelial cells in the pathogenesis of nephrolithiasis: a review

Renal tubular fluid in the distal nephron is supersaturated with calcium and oxalate ions that nucleate to form crystals of calcium oxalate monohydrate (COM), the most common crystal in renal stones. How these nascent crystals are retained in the nephron to form calculi in certain individuals is not known. Recent studies from this laboratory have demonstrated that COM crystals can bind within seconds to the apical surface of renal epithelial cells, suggesting one mechanism whereby crystals could be retained in the tubule. Adherence of crystals to cells along the nephron may be opposed by specific urinary anions such as glycosaminoglycans, uropontin, nephrocalcin, and citrate. In culture, adherent crystals are quickly internalized by renal cells, and reorganization of the cytoskeleton, alterations in gene expression, and initiation of proliferation can ensue. Each of these cellular events appears to be regulated by extracellular factors. Identification of molecules in tubular fluid and on the cell surface that determine whether a crystal-cell interaction results in retention of the crystal or its passage out of the nephron appears critical for understanding the pathogenesis of nephrolithiasis.     

The origin and evolution of viruses (a review)

Viroids and prions might have existed early at the border of inanimate and living worlds. Most extant viruses can be characterized as derivatives of ancestors originating from episomal elements of prokaryotes (DNA phages) and later from eukaryotes. Retroviruses very likely originated from cellular retrotransposons. Retrograde evolution of some large viruses from obligatory intracellular bacteria is possible but the ontogenesis of extant bacteria does not include a viral form of existence (the filterable L forms are not viruses) and well-defined viruses do not regenerate back into vegetative bacterial forms. Biologists experimenting with the evolution of prokaryotic and eukaryotic ancient cells cannot ignore the earliest appearance of viruses within or outside the living matter. Viruses participated in and gave direction to the evolution and natural selection by coexisting with uni- and multicellular organisms for billions of years. The coevolution of viruses and their host cells is characterized by incessant attacks and counterattacks through gene rearrangements and mutations (induced in the virus by an immunological counterattack of the host or by transgression of species barriers by the virus) and recombinations. Recombinations occurred between viral and viral or viral and host genes. Acts of "molecular piracy" as practiced by ancient viruses endowed the virus with the expression of several host genes for the advantage of the virus in its replicative cycle and host-to-host spread. Probably the first immortalized and malignantly transformed cells were induced by viruses as viruses evolved anti-apoptotic measures. While infected cells resort to apoptotic death before the assembly of a new viral progeny, prominent are the anti-apoptotic measures viruses evolved in order to assure the completion of their full replicative cycle. Further, viruses may escape neutralization by host antibodies and may survive a counterattack by the host's T cells directed at virally infected cells of its own. Viruses may induce a form of tolerance and coexist with their host without inducing disease. Persistent and apparently or deceivingly apathogenic or even attenuated viral "quasi-species" populations may contain individual particles that regain virulence due to recombinations and/or gene rearrangements, especially when transgressing species barriers. Xenotropic viruses of animals may replicate in human cells and vice versa confounding experiments with xenotransplants or with use of veterinary viral vaccines for the treatment of human diseases.     

The use of transplanted glial cells to reconstruct glial environments in the CNS

Transplantation studies have demonstrated that glia-depleted areas of the CNS can be reconstituted by the introduction of cultured cells. Thus, the influx of Schwann cells into glia-free areas of demyelination in the spinal cord can be prevented by the combined introduction of astrocytes and cells of the O-2A lineage. Although Schwann cell invasion of areas of demyelination is associated with destruction of astrocytes, the transplantation of rat tissue culture astrocytes ("type-1") alone cannot suppress this invasion, indicating a role for cells of the O-2A lineage in reconstruction of glial environments. By transplanting different glial cell preparations and manipulating lesions so as to prevent meningeal cell and Schwann cell proliferation it is possible to demonstrate that the behaviour of tissue culture astrocytes ("type-1") and astrocytes derived from O-2A progenitor cells ("type-2") is different. In the presence of meningeal cells, tissue culture astrocytes clump together to form cords of cells. In contrast, type-2 astrocytes spread throughout glia-free areas in a manner unaffected by the presence of meningeal cells or Schwann cells. Thus, progenitor-derived astrocytes show a greater ability to fill glia-free areas than tissue culture astrocytes. Similarly, when introduced into infarcted white matter in the spinal cord, progenitor-derived astrocytes fill the malacic area more effectively than tissue culture astrocytes, although axons do not regenerate into the reconstituted area.     

Neuroendocrine tumors and liver transplantation: review based on a case report

A case of orthotopic liver transplantation (OLT) for secondary Neuroendocrine Tumor (NET), whose primary site was not detected at the time of surgery, is reported. The primary pancreatic lesion was found 20 months later in association with recurrence of neoplasm in the graft and with a paraneoplastic syndrome peculiar of glucagonoma. The patient started octreoide therapy with a decrease of the glucagone level but without reduction of the tumor size, nor disappearance of the clinical syndrome. A few months later the primary lesion was surgically removed, but her general condition deteriorated and the patient died waiting for liver retransplantation. A discussion about the management and the diagnostic tools for preoperative staging of these neoplasms and their ability to identify the primitive and secondary location of neuroendocrine tumors is presented.