The mitochondrial HSP70 chaperone mortalin (HSPA9/GRP75) is often upregulated and mislocalized in MEK/ERK-deregulated tumors. Here, we show that mortalin depletion can selectively induce death of ...immortalized normal fibroblasts IMR90E1A when combined with K-Ras
expression, but not with wild-type K-Ras expression, and that K-Ras
-driven MEK/ERK activity is necessary for this lethality. This cell death was attenuated by knockdown or inhibition of adenine nucleotide translocase (ANT), cyclophilin D (CypD), or mitochondrial Ca
uniporter (MCU), which implicates a mitochondria-originated death mechanism. Indeed, mortalin depletion increased mitochondrial membrane permeability and induced cell death in KRAS-mutated human pancreatic ductal adenocarcinoma (PDAC) and colon cancer lines, which were attenuated by knockdown or inhibition of ANT, CypD, or MCU, and occurred independently of TP53 and p21
. Intriguingly, JG-98, an advanced MKT-077 derivative, phenocopied the lethal effects of mortalin depletion in K-Ras
-expressing IMR90E1A and KRAS-mutated tumor cell lines in vitro. Moreover, JG-231, a JG-98 analog with improved microsomal stability effectively suppressed the xenograft of MIA PaCa-2, a K-Ras
-expressing human PDAC line, in athymic nude mice. These data demonstrate that oncogenic KRAS activity sensitizes cells to the effects of mortalin depletion, suggesting that mortalin has potential as a selective therapeutic target for KRAS-mutated tumors.
In an effort for early assessment of treatment response, we investigate radiation induced changes in quantitative CT features of tumor during the delivery of chemoradiation therapy (CRT) for ...pancreatic cancer.
Diagnostic-quality CT data acquired daily during routine CT-guided CRT using a CT-on-rails for 20 pancreatic head cancer patients were analyzed. On each daily CT, the pancreatic head, the spinal cord and the aorta were delineated and the histograms of CT number (CTN) in these contours were extracted. Eight histogram-based radiomic metrics including the mean CTN (MCTN), peak position, volume, standard deviation (SD), skewness, kurtosis, energy and entropy were calculated for each fraction. Paired t-test was used to check the significance of the change of specific metric at specific time. GEE model was used to test the association between changes of metrics over time for different pathology responses.
In general, CTN histogram in the pancreatic head (but not in spinal cord) changed during the CRT delivery. Changes from the 1st to the 26th fraction in MCTN ranged from -15.8 to 3.9 HU with an average of -4.7 HU (p<0.001). Meanwhile the volume decreased, the skewness increased (less skewed), and the kurtosis decreased (less peaked). The changes of MCTN, volume, skewness, and kurtosis became significant after two weeks of treatment. Patient pathological response is associated with the changes of MCTN, SD, and skewness. In cases of good response, patients tend to have large reductions in MCTN and skewness, and large increases in SD and kurtosis.
Significant changes in CT radiomic features, such as the MCTN, skewness, and kurtosis in tumor were observed during the course of CRT for pancreas cancer based on quantitative analysis of daily CTs. These changes may be potentially used for early assessment of treatment response and stratification for therapeutic intensification.
Venous invasion is three times more common in pancreatic cancer than it is in other major cancers of the gastrointestinal tract, and venous invasion may explain why pancreatic cancer is so deadly. To ...characterize the patterns of venous invasion in pancreatic cancer, 52 thick slabs (up to 5 mm) of tissue were harvested from 52 surgically resected human ductal adenocarcinomas, cleared with a modified iDISCO method, and labeled with fluorescent-conjugated antibodies to cytokeratin 19, desmin, CD31, p53 and/or e-cadherin. Labeled three-dimensional (3D) pancreas cancer tissues were visualized with confocal laser scanning or light sheet microscopy. Multiple foci of venous and even arterial invasion were visualized. Venous invasion was detected more often in 3D (88%, 30/34 cases) than in conventional 2D slide evaluation (75%, 25/34 cases, P < 0.001). 3D visualization revealed pancreatic cancer cells crossing the walls of veins at multiple points, often at points where preexisting capillary structures bridge the blood vessels. The neoplastic cells often retained a ductal morphology (cohesive cells forming tubes) as they progressed from a stromal to intravenous location. Although immunolabeling with antibodies to e-cadherin revealed focal loss of expression at the leading edges of the cancers, the neoplastic cells within veins expressed e-cadherin and formed well-oriented glands. We conclude that venous invasion is almost universal in pancreatic cancer, suggesting that even surgically resectable PDAC has access to the venous spaces and thus the ability to disseminate widely. Furthermore, we observe that sustained epithelial-mesenchymal transition is not required for venous invasion in pancreatic cancer.
Liver dysfunction occurs in up to 3% of pregnancies and can be due to pregnancy‐associated liver injury, exacerbation of pre‐existing liver disease, or co‐incident with pregnancy. The most common ...form of pregnancy‐associated liver injury is intrahepatic cholestasis of pregnancy (ICP). This condition is typically benign and self‐limited, but is associated with fetal morbidity and mortality with high levels of serum bile acids. Acute fatty liver of pregnancy (AFLP) and the hypertensive disorders of pregnancy (including pre‐eclampsia, eclampsia, and hemolysis, elevated liver enzymes, and low platelets HELLP syndrome) are more commonly associated with maternal and fetal complications and may necessitate expedient delivery. Histologically, ICP shows nonspecific features of cholestasis, while AFLP and the hypertensive disorders have more characteristic histologic findings. While not a true liver disease, hyperemesis gravidarum can cause elevated liver enzymes. Pregnant patients are at increased risk of developing severe hepatitis E and herpesvirus infections, Budd–Chiari syndrome, and gallstones, and they may also experience worsening of known chronic liver disease. Mass lesions in pregnancy including hemangiomas, focal nodular hyperplasia, and hepatocellular adenomas and carcinomas can present unique challenges for diagnosis and management. This review will explore the pathophysiology, presentation, histologic features, and management of these conditions.
Cancerization of ducts in hilar cholangiocarcinoma Lee, Jae W.; Zhang, Yang; Yoshizawa, Tadashi ...
Virchows Archiv : an international journal of pathology,
08/2022, Volume:
481, Issue:
2
Journal Article
Peer reviewed
Invasive cancers that arise from ductal structures can infiltrate and colonize pre-existing ducts in a process referred to as cancerization of ducts (COD). COD in cholangiocarcinoma is an ...under-studied process whose clinical significance remains poorly understood. Even though both cancerized ducts and biliary intraepithelial neoplasias (BilINs) show dysplastic changes, hallmarks of COD are (i) an abrupt transition from the normal/reactive epithelium to severe dysplasia and (ii) close proximity to invasive carcinoma with similar cytologic features. We investigated 113 cases of surgically resected hilar cholangiocarcinoma and identified COD in 37 cases (33%). Using immunohistochemistry, we found that COD and adjacent invasive carcinoma had a concordant pattern of p53 and SMAD4 staining in 95% (21/22) and 100% (21/21) of cases, respectively. In contrast, BilINs and cancerized ducts showed significantly lower levels of concordance in p53 and SMAD4 staining at 44% (8/18) and 47% (8/17) of cases, respectively (
P
= 0.0007 and 0.0001, respectively). By univariate analysis, positive lymph node metastasis (
P
= 0.027), positive final bile duct margin (
P
= 0.021), and the presence of COD (
P
= 0.020) were associated with decreased overall survival. We further performed multivariate analysis to demonstrate that positive lymph node metastasis (
P
= 0.031), positive final bile duct margin (
P
= 0.035), and COD (
P
= 0.0051) were correlated with decreased overall survival. Together, our study highlights that COD is a clinically significant process in hilar cholangiocarcinoma that can be identified using morphological criteria in conjunction with p53 and SMAD4 immunolabeling.
We previously showed that black raspberries (BRBs) have beneficial effects in human colorectal cancer and a mouse model of colorectal cancer (Apc
). The current study investigated the role of free ...fatty acid receptor 2 (FFAR2) in colon carcinogenesis and whether the FFAR2 signaling pathway contributes to BRB-mediated chemoprevention in mice. FFAR2 (also named GPR43) is a member of the G-protein-coupled receptor family that is expressed in leukocytes and colon. Apc
and Apc
-FFAR2
mice were given a control diet or the control diet supplemented with 5% BRBs for 8 weeks. FFAR2 deficiency promoted colonic polyp development, with 100% incidence and increased polyp number and size. The Apc
mice developed colonic tubular adenoma, whereas the Apc
-FFAR2
mice developed colonic tubular adenoma with high-grade dysplasia. FFAR2 deficiency also enhanced the cAMP-PKA-CREB-HDAC pathway, downstream of FFAR2 signaling, and increased activation of the Wnt pathway, and raised the percentage of GR-1
neutrophils in colonic lamina propria (LP) and increased infiltration of GR-1
neutrophils into colonic polyps. BRBs suppressed colonic polyp development and inhibited the cAMP-PKA-CREB-HDAC and Wnt pathways in the Apc
mice but not the Apc
-FFAR2
mice. They also increased the percentage of GR-1
neutrophils and cytokine secretion in colonic LP and decreased the infiltration of GR-1
neutrophils and IL-1β expression in colon polyps of Apc
mice but not Apc
-FFAR2
mice. These results suggest that loss of FFAR2 drives colon tumorigenesis and that BRBs require functional FFAR2 to be chemopreventive. BRBs have the potential to modulate the host immune system, thereby enhancing the antitumor immune microenvironment.
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