Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.).
The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of inducing angiogenesis, some cancers vascularize by the non-angiogenic mechanism of vessel co-option. Here we show that vessel co-option is associated with a poor response to the anti-angiogenic agent bevacizumab in patients with colorectal cancer liver metastases. Moreover, we find that vessel co-option prevails in human breast cancer liver metastases, a setting where results with anti-angiogenic therapy have been disappointing. In our preclinical mechanistic studies, we show that cancer cell motility mediated by the Arp2/3 complex is required for vessel co-option in liver metastases in vivo and that combined inhibition of angiogenesis and vessel co-option is more effective than inhibiting angiogenesis alone in this setting. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option may be a warranted therapeutic strategy.
Background:Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs.Methods:Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined.Results:Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006).Conclusions:The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies.
We propose that prolonged CMV causes diaphragm disuse, which, in turn, leads to activation of the ALP through oxidative stress and the induction of the FOXO1 transcription factor.
We have developed a panel of rabbit polyclonal antipeptide antibodies against the five human somatostatin receptor subtypes (hSSTR1-5) and used them to analyze the pattern of expression of hSSTR1-5 in normal human islet cells by quantitative double-label confocal fluorescence immunocytochemistry. All five hSSTR subtypes were variably expressed in islets. The number of SSTR immunopositive cells showed a rank order of SSTR1 > SSTR5 > SSTR2 > SSTR3 > SSTR4. SSTR1 was strongly colocalized with insulin in all beta-cells. SSTR5 was also an abundant isotype, being colocalized in 87% of beta-cells. SSTR2 was found in 46% of beta-cells, whereas SSTR3 and SSTR4 were relatively poorly expressed. SSTR2 was strongly colocalized with glucagon in 89% of alpha-cells, whereas SSTR5 and SSTR1 colocalized with glucagon in 35 and 26% of alpha-cells, respectively. SSTR3 was detected in occasional alpha-cells, and SSTR4 was absent. SSTR5 was preferentially expressed in 75% of SST-positive cells and was the principal delta-cell SSTR subtype, whereas SSTR1-3 were colocalized in only a few delta-cells, and SSTR4 was absent. These studies reveal predominant expression of SSTR1, SSTR2, and SSTR5 in human islets. Beta-cells, alpha-cells, and delta-cells each express multiple SSTR isoforms, beta-cells being rich in SSTR1 and SSTR5, alpha-cells in SSTR2, and delta-cells in SSTR5. Although there is no absolute specificity of any SSTR for an islet cell type, SSTR1 is beta-cell selective, and SSTR2 is alpha-cell selective. SSTR5 is well expressed in beta-cells and delta-cells and moderately well expressed in alpha-cells, and thereby it lacks the islet cell selectivity displayed by SSTR1 and SSTR2. Subtype-selective SSTR expression in islet cells could be the basis for preferential insulin suppression by SSTR1-specific ligands and of glucagon inhibition by SSTR2-selective compounds.
Proproteins are the fundamental units from which bioactive proteins and peptides are derived by limited proteolysis. Precursors are usually cleaved at the general motif (K/R)X n (K/ R)2, where n ϭ 0, 2, 4, or 6 and X is usually not a Cys. Seven dibasic specific mammalian proprotein convertases (PCs) 1 have been identified: furin, PC1/PC3, PC2, PC4, PACE4, PC5/PC6, and PC7/LPC/PC8. Each of these enzymes, either alone or in combination with others, is responsible for the tissue-specific processing of multiple polypeptide precursors. This combinatorial mechanism generates a large diversity of bioactive molecules in an exquisitely regulated manner (1-4). Some of these precursors include adhesion molecules, e.g. integrin ␣-subunits (5); matrix metalloproteinases (MMPs) such as stromelysin-3 and membrane-type MMPs (MT-MMPs) (6, 7); several growth factor precursors, including transforming growth factor- (8, 9), insulin-like growth factor-1 (IGF-1), and IGF-2 (10 -12); and some growth factor proreceptors such as the insulin receptor (13) and phosphotyrosine phosphatase (14).Recently, the potential clinical and pharmacological role of the convertases fostered the development of both peptide-and protein-based PC inhibitors (for reviews, see Refs. 1-4). The most promising protein-based specific inhibitors of PCs is an ␣ 1 -antitrypsin variant known as ␣ 1 -antitrypsin Portland (␣ 1 -PDX) (15-17) and the individual PC prosegment-based inhibitors (18). Recent studies showed that inhibition of PCs by ␣ 1 -PDX reduces the production level of the amyloid precursor ␣-secretase product -amyloid precursor protein-␣ (19) and blocks the activation of the pore-forming toxin proaerolysin (20), the cleavage of Notch (21), the proteolytic activation of bone morphogenic factor-4 (22), and the maturation of the surface glycoproteins of infectious viruses (15,17,23 1 The abbreviations used are: PCs, proprotein convertases; MMP, matrix metalloproteinase; MT-MMP, membrane-type matrix metalloproteinase; IGF, insulin-like growth factor; IGF-1R, insulin-like growth factor-1 receptor; ␣ 1 -PDX, ␣ 1 -antitrypsin Portland; uPA, urokinasetype plasminogen activator; uPAR, urokinase-type plasminogen activator receptor; tPA, tissue-type plasminogen activator; PAI-1, plasminogen activator inhibitor-1; IRS-1, insulin-related substrate-1; FCS, fetal calf serum; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; bp, base pair; SKI-1, subtilisin kexin isozyme-1.
The liver represents the third most frequent site of metastasis in patients with breast cancer. We performed in vivo selection using 4T1 breast cancer cells to identify genes associated with the liver metastatic phenotype. Coincident with the loss of numerous tight-junctional proteins, we observe claudin-2 overexpression, specifically in liver-aggressive breast cancer cells. We further demonstrate that claudin-2 is both necessary and sufficient for the ability of 4T1 breast cancer cells to colonize and grow in the liver. The liver-aggressive breast cancer cells display a claudin-2-mediated increase in their ability to adhere to extracellular matrix (ECM) components, such as fibronectin and type IV collagen. Claudin-2 facilitates these cell/matrix interactions by increasing the cell surface expression of a 2 b 1 -and a 5 b 1 -integrin complexes in breast cancer cells. Indeed, claudin-2-mediated adhesion to fibronectin and type IV collagen can be blocked with neutralizing antibodies that target a 5 b 1 and a 2 b 1 complexes, respectively. Immunohistochemical analyses reveal that claudin-2, although weakly expressed in primary human breast cancers, is readily detected in all liver metastasis samples examined to date. Together, these results uncover novel roles for claudin-2 in promoting breast cancer adhesion to the ECM and define its importance during breast cancer metastasis to the liver.
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