Tissue invasion and metastasis: Molecular, biological and clinical perspectives.

Cancer is a key health issue across the world, causing substantial patient morbidity and mortality. Patient prognosis is tightly linked with metastatic dissemination of the disease to distant sites, with metastatic diseases accounting for a vast percentage of cancer patient mortality. While advances in this area have been made, the process of cancer metastasis and the factors governing cancer spread and establishment at secondary locations is still poorly understood. The current article summarizes recent progress in this area of research, both in the understanding of the underlying biological processes and in the therapeutic strategies for the management of metastasis. This review lists the disruption of E-cadherin and tight junctions, key signaling pathways, including urokinase type plasminogen activator (uPA), phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT), focal adhesion kinase (FAK), ß-catenin/zinc finger E-box binding homeobox 1 (ZEB-1) and transforming growth factor beta (TGF-ß), together with inactivation of activator protein-1 (AP-1) and suppression of matrix metalloproteinase-9 (MMP-9) activity as key targets and the use of phytochemicals, or natural products, such as those from Agaricus blazei, Albatrellus confluens, Cordyceps militaris, Ganoderma lucidum, Poria cocos and Silybum marianum, together with diet derived fatty acids gamma linolenic acid (GLA) and eicosapentanoic acid (EPA) and inhibitory compounds as useful approaches to target tissue invasion and metastasis as well as other hallmark areas of cancer. Together, these strategies could represent new, inexpensive, low toxicity strategies to aid in the management of cancer metastasis as well as having holistic effects against other cancer hallmarks.

Interactions of fluorochrome-labeled caspase inhibitors with apoptotic cells: a caution in data interpretation.

BACKGROUND: Fluorochrome-labeled inhibitors of caspases (FLICA, e.g., FAM-VAD-FMK, FITC-VAD-FMK) have been designed as affinity labels of the enzyme active center of caspases Their binding by apoptotic cells was interpreted as reflecting activation of caspases. We have recently observed, however, that their binding is more complex and may involve additional mechanisms. Our goal in this study was to clarify the ongoing utility of these probes. METHODS: Apoptosis of HL-60, Jurkat, MCF-7 and T-24 cells was induced by the DNA topoisomerase I inhibitor, topotecan, or by oxidative stress (H(2)O(2)). Lymphocytes were induced by their mitogenic activation. Using multiparameter laser scanning and flow cytometry analysis, the correlation between FLICA binding and the number of known apoptotic indicators was examined. These included: collapse of the mitochondrial transmembrane potential; activation of caspase-3 (detected immunocytochemically); binding of annexin V; chromatin condensation; the presence of DNA strand breaks; and loss of plasma membrane capability to exclude propidium iodide (PI). FLICA binding specificity was tested by pretreatment with z-VAD-FMK or z-DEVD-FMK. RESULTS: FLICA binding was subsequent to the collapse of mitochondrial transmembrane potential, nearly concurrent with caspase-3 activation, and preceded annexin V binding, chromatin condensation, DNA fragmentation and loss of plasma membrane integrity. The predominant portion of FAM-VAD-FMK, FITC-VAD-FMK or FAM-DEVD-FMK binding to apoptotic cells could not be inhibited by z-VAD-FMK or z-DEVD-FMK, respectively, when the unlabeled inhibitors were added post-induction of apoptosis. CONCLUSIONS: FLICA are specific and convenient to use markers of apoptotic cells and they detect very early events of apoptosis associated with caspases activation. Assays that combine their binding with either the loss of mitochondrial potential or with exclusion of PI as a probe of plasma membrane integrity, distinguish sequential stages of apoptosis and are particularly useful to differentiate between apoptosis and necrosis. Our results conform with the published data that unlabeled caspase inhibitors, when added after induction of apoptosis, cannot prevent activation of caspases detected by binding of biotinylated inhibitors or by cleavage of fluorogenic substrates. While FLICA binding by apoptotic cells most likely is a consequence of caspase activation, these binding events may also involve other or additional mechanisms than simply their specific attachment to the active enzyme centers of caspases.

Enhancement of activation-induced apoptosis of lymphocytes by the cytotoxic ribonuclease onconase (Ranpirnase).

Onconase (Onc) is an amphibian ribonuclease of the pancreatic RNase family that is cytostatic and cytotoxic to several tumor lines. It also shows anti-tumor activity in mouse tumor models and is currently in phase III clinical trials. In animal tests and clinical trials Onc shows lesser toxicity and fewer side effects compared to most chemotherapeutic drugs. Intriguingly, repeated infusions of this protein do not cause apparent immunological reactions in patients. The aim of the present study was to investigate sensitivity to Onc of human lymphocytes during their mitogenic stimulation in response to the polyvalent mitogen phytohemagglutinin (PHA), and in mixed allogeneic lymphocyte cultures. Unexpectedly, we observed that frequency of cells undergoing activation-induced apoptosis was markedly increased in all cultures containing Onc. Apoptosis was measured by flow cytometry using markers that detect activation of caspases, the in situ presence of DNA strand breaks, and loss of fragmented DNA ('sub-G1' cell subpopulation). The enhancement of frequency of activation-induced apoptosis (up to 244%) was observed at 4.2-83 nM Onc concentration, which is at least an order magnitude lower than its minimal concentration reported to affect proliferation or induce apoptosis of leukemic and solid tumor cell lines. The cell cycle progression of lymphocytes that responded to PHA mitogenically was not affected at 8.3 or 83 nM Onc concentration. Because activation-induced apoptosis is the key mechanism regulating several in vivo immunological functions including induction of tolerance, the observed effects of Onc may explain the apparent lack of immune reactions to this protein in treated patients. The propensity of Onc to potentiate the activation-induced apoptosis suggests that this drug may have clinical utility as immunomodulating agent, e.g., to suppress transplant rejection or treat autoimmune diseases.

[Emotional disorders in patients with multiple sclerosis]. / Zaburzenia emocjonalne u chorych na stwardnienie rozsiane.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system, especially young adults. Although MS is usually looked on as a disorder of the sensory and motor systems it can also be associated with emotional dysfunctions and changes in personality. The depression, bipolar disorders, euphoria, and pathological laughing and crying are most frequently associated with the disease. Authors present a review of current opinions on pathogenesis, diagnostic criteria and treatment of emotional problems in MS patients.

[Frontotemporal dementias]. / Demencje czolowo-skroniowe.

Frontotemporal dementias are the second largest degenerative dementia group after Alzheimer's disease. It is a clinical syndrome corresponding to at least three histological entities: Pick's disease, non-specific frontotemporal degeneration, frontal lobe abnormalities associated with motor neuron disease. There are four group of symptoms in the clinical description of FTD: behavioural disorder, affective symptoms, speech disorders, neurological signs. FTD is associated with primary degeneration of the frontal and temporal lobes. Histologically there was neuronal loss, microvacuolation, tau- and ubiquitin-immunoreactive inclusions. The ballooned cortical neurons and tau- and ubiquitin-immunoreactive, argyrophilic inclusions have been called Pick-type histology. There are many descriptions of association of FTD and Pick's disease with motor neuron disease and amyotrophic lateral sclerosis. Histological changes were similar to cortical ones. In this study, we described clinical characteristic features of frontotemporal dementia and difficulties in its identification. The distinctive histopathological pattern in the FTD patients and its value to differentiate frontotemporal degeneration from other degenerative dementias is discussed.

[Neurologic and psychiatric sequelae of carbon monoxide poisoning]. / Neurologiczne i psychiatryczne nastepstwa zatrucia tlenkiem wegla.

Carbon monoxide intoxication may result in neuropsychiatric abnormalities that can be overlooked or not fully appreciated. The authors describe two female patients who developed troublesome cognitive and emotional problems following carbon monoxide poisoning and stress the value of the precise neuropsychological testing and prolonged clinical observation in such cases.

[Cortico-basal degeneration]. / Zwyrodnienie korowo-podstawne.

Cortico-basal degeneration (CBD) or cortico-basal ganglionic degeneration is a condition characterised by selective cortical atrophy of parietal and in a lesser extent, frontal lobe associated with dysfunction of the basal ganglia. The clinical symptoms of CBD, predominantly extrapyramidal signs (bradykinesia and rigidity) and apraxia, affect often only one body side in the onset phase, with the left one being more frequent. Neuropathological studies reveal neuronal loss, gliosis, and achromasia chiefly in frontal and parietal cortex, as well as in basal ganglia and substantia nigra. Functional investigations, such as SPECT, disclose similar distribution of abnormalities (hypometabolism). The aetiology and causative treatment of CBD are unknown. The authors highlight the diagnostic difficulties in CBD including a necessity of a prolonged patient's observation in order to ascertain the differential diagnosis of other neurodegenerative disorders, in particular progressive supranuclear palsy, Alzheimer's disease and Parkinson's disease.

[Subcortical infarcts (caudate nucleus) in a case of bilateral anterior cerebral artery occlusion]. / Zawaly podkorowe (jadra ogoniastego) w przypadku obustronnej niedroznosci tetnic mózgu przednich.

The authors describe a patient with bilateral anterior cerebral artery (ACA) occlusion. CT and MRI revealed bilateral encephalomalacia in the regions supplied by Heubner arteries and/or by perforating branches of ACA. The patient presented mainly with frontal symptomatology resulting from caudate nuclei lesion. Frontal symptomatology due to caudate impairment is discussed in the sense of frontal-subcortical circuits: lateral orbitofrontal and anterior cingulate ones. We emphasise a similarity of behavioural and cognitive disorders in early Huntington's disease and in frontal lobe lesion.

[Subcortical dementia and the frontal lobe syndrome]. / Demencja podkorowa a zespól czolowy.

Subcortical dementia is a clinical syndrome incorporating disorders of cognitive and affective sphere, which is caused by organic damage to subcortical structures. The syndrome is usually connected with Progressive Supranuclear Palsy, Huntington Disease, Parkinson's Disease. Subcortical dementia is mainly characterized by: slowing down of psychic functions and impairment of their precision, disorders in the ability to use achieved knowledge and personality changes. Most authors stress the fact that similar cognitive and emotional personality defects are observed in cases of frontal cortex damage. Recent research points to the existence of functional subcortical-prefrontal circuits which regulate human behaviour. There is a link between subcortical dementia and functional or structural break of one or more cortical-subcortical connections. Attention is also called to disorders in certain neurotransmitting systems (dopaminergic, acetylcholinergic) as well as to brain hypometabolism in basal ganglia, thalamus and prefrontal cortex.