Pathogenesis,clinical and laboratory aspects of thrombosis in cancer

The relationship between increased clotting and malignancy is well recognized, though the bidirectional development of this association is often overlooked. In the challenging cancer biology, transforming genes often act in concert with numerous epigenetic factors, including hypoxia, inflammation, contact between blood and cancer cells, and emission of procoagulant vesicles from tumors, to determine a net imbalance of the hemostatic potential which is detectable by a variety of laboratory tests. Procoagulant factors, in particular, are intimately involved in all aspects of hemostatic, cell proliferation and cellular signalling systems. However, the biggest as yet unresolved question is why cancer patients develop thrombosis? Since the thrombus itself does not apparently contributes directly to the tumor biology, enhanced hemostasis activation in cancer patients may be interpreted according to the most recent biological evidences. Coagulation and cancer biology interact bidirectionally in a “vicious cycle”, in which greater tumor burden supplies greater procoagulants (tissue factor, cancer procoagulant) and thrombin, which would in turn act as strong promoters of cancer growth and spread. In this perspective, thrombosis may be interpreted as a epiphenomenon of an intricate an effective biological feedback to maintain or promote cancer progression. In this review article, we briefly analyze the pathogenesis, laboratory, clinical and therapeutic features of cancer and thrombosis.     

Norepinephrine promotes tumor microenvironment reactivity through β3-adrenoreceptors during melanoma progression

Stress has an emerging role in cancer and targeting stress-related β-adrenergic receptors (AR) has been proposed as a potential therapeutic approach in melanoma. Here we report that β3-AR expression correlates with melanoma aggressiveness. In addition, we highlight that β3-AR expression is not only restricted to cancer cells, but it is also expressed in vivo in stromal, inflammatory and vascular cells of the melanoma microenvironment. Particularly, we demonstrated that β3-AR can (i) instruct melanoma cells to respond to environmental stimuli, (ii) enhance melanoma cells response to stromal fibroblasts and macrophages, (iii) increase melanoma cell motility and (iv) induce stem-like traits. Noteworthy, β3-AR activation in melanoma accessory cells drives stromal reactivity by inducing pro-inflammatory cytokines secretion and de novo angiogenesis, sustaining tumor growth and melanoma aggressiveness. β3-ARs also play a mandatory role in the recruitment to tumor sites of circulating stromal cells precursors, in the differentiation of these cells towards different lineages, further favoring tumor inflammation, angiogenesis and ultimately melanoma malignancy. Our findings validate selective β3-AR antagonists as potential promising anti-metastatic agents. These could be used to complement current therapeutic approaches for melanoma patients (e.g. propranolol) by targeting non-neoplastic stromal cells, hence reducing therapy resistance of melanoma.     

Activation of an endothelial Notch1-Jagged1 circuit induces VCAM1 expression,an effect amplified by interleukin-1β

The Notch1 and Notch4 signaling pathways regulate endothelial cell homeostasis. Inflammatory cytokines induce the expression of endothelial adhesion molecules, including VCAM1, partly by downregulating Notch4 signaling. We investigated the role of endothelial Notch1 in this IL-1β-mediated process. Brief treatment with IL-1β upregulated endothelial VCAM1 and Notch ligand Jagged1. IL-1β decreased Notch1 mRNA levels, but levels of the active Notch1ICD protein remained constant. IL-1β-mediated VCAM1 induction was downregulated in endothelial cells subjected to pretreatment with a pharmacological inhibitor of the γ-secretase, which activates Notch receptors, producing NotchICD. It was also downregulated in cells in which Notch1 and/or Jagged1 were silenced.Conversely, the forced expression of Notch1ICD in naïve endothelial cells upregulated VCAM1 per se and amplified IL-1β-mediated VCAM1 induction. Jagged1 levels increased and Notch4 signaling was downregulated in parallel. Finally, Notch1ICD and Jagged1 expression was upregulated in the endothelium of the liver in a model of chronic liver inflammation.In conclusion, we describe here a cell-autonomous, pro-inflammatory endothelial Notch1-Jagged1 circuit (i) triggering the expression of VCAM1 even in the absence of inflammatory cytokines and (ii) enhancing the effects of IL-1β. Thus, IL-1β regulates Notch1 and Notch4 activity in opposite directions, consistent with a selective targeting of Notch1 in inflamed endothelium.     

Monosomy of chromosome 17 in breast cancer during interpretation of HER2 gene amplification

Monosomy of chromosome 17 may affect the assessment of HER2 amplification. Notably, the prevalence ranges from 1% up to 49% due to lack of consensus in recognition. We sought to investigate the impact of monosomy of chromosome 17 to interpretation of HER2 gene status. 201 breast carcinoma were reviewed for HER2 gene amplification and chromosome 17 status. FISH analysis was performed by using double probes (LSI/CEP). Absolute gene copy number was also scored per each probe. HER2 FISH test was repeated on serial tissue sections, ranging in thickness from 3 to 20 µm. Ratio was scored and subsequently corrected by monosomy after gold control test using the aCGH method to overcome false interpretation due to artefactual nuclear truncation. HER2 immunotests was performed on all cases. 26/201 cases were amplified (13%). Single signals per CEP17 were revealed in 7/201 (3.5%) cases. Five out of 7 cases appeared monosomic with aCGH (overall, 5/201, 2.5%) and evidenced single signals in >60% of nuclei after second-look on FISH when matching both techniques. Among 5, one case showed amplification with a pattern 7/1 (HER2/CEP17>2) of copies (3+ at immunotest); three cases revealed single signals per both probes (LSI/CEP=1) and one case revealed a 3:1 ratio; all last 4 cases showed 0/1+ immunoscore. We concluded that: 1) monosomy of chromosome 17 may be observed in 2.5% of breast carcinoma; 2) monosomy of chromosome 17 due to biological reasons rather than nuclear truncation was observed when using the cut-off of 60% of nuclei harboring single signals; 3) the skewing of the ratio due to single centromeric 17 probe may lead to false positive evaluation; 4) breast carcinomas showing a 3:1 ratio (HER2/CEP17) usually show negative 0/1+ immunoscore and <6 gene copy number at FISH.     

Brainstem Auditory Evoked Potentials (BAEPs) in Childhood Migraine

SYNOPSIS
Brainstem auditory evoked potentials (BAEPs) were recorded in pain-free periods in 28 children suffering from migraine (23 common and 5 classic). They were without medication for at least one month before there cording session. The results were compared with a group of 10 normal subjects matched for sex and age. We found no significant differences between the migraine group and the control subjects; when analyzing separately the classic and common form, two groups either with more or less than 5 years of history of migraine or with and without nausea and/or vomiting, similar results were obtained. Our data suggest that in migrainous children conduction in the auditory pathway at the brainstem level is not significantly different from controls.     

Adult-onset leukodystrophies from respiratory chain disorders: do they exist?

Respiratory chain disorders (RCDs) have been included in the differential diagnosis of adult-onset leukodystrophies. Here, we first report a 32-year-old female with an atypical, adult-onset, non-syndromic RCD due to a mitochondrial DNA deletion and manifesting as complicated ataxia. A ‘leukodystrophic’ pattern was found on brain MRI, but it was neither isolated nor predominant because of the presence of overt basal ganglia and infratentorial lesions, which led us to the proper diagnosis. Subsequently, we evaluated our series of patients with RCDs in order to verify whether a ‘leukodystrophic’ pattern with little or no involvement of deep grey structures and brainstem may be found in adult-onset RCDs, as reported in children. Among 52 patients with adult-onset RCDs, no case with a ‘leukodystrophic’ pattern was found, apart from three cases with a classical phenotype of mitochondrial neurogastrointestinal encephalopathy. In addition, no case of RCDs was found among six cases of adult-onset leukodystrophy of unknown origin and at least one feature suggestive of mitochondrial disease. The review of the literature was in agreement with these findings. Thus, we provide evidence that, unlike in children, RCDs should not be included in the differential diagnosis of adult-onset leukodystrophies, except when there are additional MRI findings or clinical features which unequivocally point towards a mitochondrial disorder.