The CD274 (PD-L1)/PDCD1 (PD-1) pathway is crucial for the modulation of immune responses and self-tolerance. Aberrantly expressed CD274 allows tumor cells to evade host immune system and is ...considered to be a mechanism of adaptive immune resistance. Inhibition of the CD274/PDCD1 immune checkpoint offers a promising new therapeutic strategy. Although CD274-expressing tumor cells have been identified in different types of tumors including colorectal cancer, clinicopathologic profile of these CD274-positive tumors has not been extensively studied. In this study, 454 primary colorectal carcinomas were analyzed histologically and immunohistochemically for CD274, mismatch repair (MMR) proteins, intestinal differentiation marker (CDX2), and stem cell markers (ALCAM, ALDH1A1, and SALL4). CD274-positive colorectal carcinomas (54/454 (12%)) usually (83%) involved the right or transverse colon with poorly differentiated and solid/medullary histology. On the basis of multivariate logistic regression analysis, CD274 positivity was significantly associated with poorly differentiated histotype (OR: 3.32; 95% CI: 1.46-7.51; P=0.004), MMR deficiency (OR: 10.0; 95% CI: 4.66-21.5; P<0.001), and 'stem-like' immunophenotype defined by the loss or weak expression of CDX2 and ALCAM-positivity (OR: 5.51; 95% CI: 1.66-18.3; P=0.005). Mutation analysis of 66 arbitrary selected colorectal carcinomas revealed that CD274-positive tumors usually (88%) carried the BRAF V600E mutation. Thus, colorectal carcinomas defined by CD274 positivity displayed features associated with tumors arising via the serrated neoplasia pathway. Moreover, colorectal carcinomas characterized by lack of CDX2 and prominent expression of ALCAM frequently (71%) showed CD274 positivity. This might suggest association of CD274 expression with 'stem-like' phenotype. Further evaluation of a larger cohort or experimental analyses would be needed to confirm this notion.
We detected Helicobacter cinaedi in 4 of 10 patients with infected aortic aneurysms diagnosed using blood or tissue culture in Aichi, Japan, during September 2017–January 2021. Infected aortic ...aneurysms caused by H. cinaedi had a higher detection rate and better results after treatment than previously reported, without recurrent infection.
Cell motility is a tightly regulated phenomenon that supports the accurate formation of organ structure during development and homeostasis, including wound healing and inflammation. Meanwhile, cancer ...cells exhibit dysregulated motility, which causes spreading and invasion. The Dbl family RhoGEF ARHGEF7/β-PIX and its binding partner p21-activated kinase PAK1 are overexpressed in a variety of cancers and have been shown to be responsible for cancer cell migration. A key step in motility is the intracellular transport of ARHGEF7-PAK1 complex to the migrating front of cells, where lamellipodia protrusion and cytoskeletal remodeling efficiently occur. However, the molecular mechanisms of the intracellular transport of this complex are not fully understood. Here we revealed that SCL/TAL1-interrupting locus (STIL) is indispensable for the efficient migration of cancer cells. STIL forms a ternary complex with ARHGEF7 and PAK1 and accumulates with those proteins at the lamellipodia protrusion of motile cells. Knockdown of STIL impedes the accumulation of ARHGEF7-PAK1 complex within membrane ruffles and attenuates the phosphorylation of PAK1 substrates and cortical actin remodeling at the migrating front. Intriguingly, ARHGEF7 knockdown also diminishes STIL and PAK1 accumulation in membrane ruffles. Either STIL or ARHGEF7 knockdown impedes cell migration and Rac1 activity at the migrating front of cells. These results indicate that STIL is involved in the ARHGEF7-mediated positive-feedback activation of cytoskeletal remodeling through accumulating the ARHGEF7-PAK1 complex in lamellipodia. We conclude that its involvement is crucial for the polarized formation of Rac1-mediated leading edge, which supports the efficient migration of cancer cells.
The anticancer effects of immune checkpoint inhibitors against CTLA4 and CD274-PDCD1 axes are evident. However, these immunotherapies for colorectal cancers (CRCs) are now limited to a small subset ...of patients with microsatellite unstable tumors. Thus, therapeutics targeting other types of CRCs is desired. The CD70–CD27 axis plays a co-stimulatory role in promoting the expansion and differentiation of T-lymphocytes through the activation of NFκB pathway. Aberrant activation of the CD70–CD27 axis accelerates tumor cell proliferation, survival, and immune evasion of tumor cells. Based on these observations, drugs modulating the CD70–CD27 axis have been developed with expectation of anticancer effects. In the present study, 269 primary CRCs were evaluated immunohistochemically for CD70, CD27, and FOXP3 expression to assess their clinical usage and the application of CD70–CD27 axis modulating drugs. CRC tumor cells rarely (2.2%) expressed CD70. In contrast, tumor-surrounding fibroblasts showed various CD70 expressions (fCD70) in 14.9%. The logistic regression analysis revealed significant association of fCD70 expression with incomplete resection status (OR, 2.60; 95% CI, 1.10–6.13;
P
= 0.029). Overall survival was significantly decreased in the cohort of the patients with fCD70-positive tumor (
P
= 0.0078). Furthermore, significantly more CD27+ tumor-associated lymphocytes were detected within the primary CRCs without metastases (
P
= 0.024). Thus, the CD70–CD27 axis may have several roles in CRCs independent from their mismatch repair (MMR) system status. CD70–CD27 pathway-modulating therapies may be applied to CRC patients regardless of their tumor MMR status.
Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide with high morbidity and mortality rates. The discovery of small molecule anticancer reagents has significantly ...affected cancer therapy. However, the anticancer effects of these therapies are not sufficient to completely cure CRC. PDZ-binding kinase (PBK) was initially identified as a mitotic kinase for mitogen-activated protein kinase and is involved in cytokinesis and spermatogenesis. Aberrant expression of PBK has been reported to be closely associated with malignant phenotypes of many cancers and/or patient survival. However, the expression of PBK and its association to patient survival in CRC have not been fully elucidated. In the present study, 269 primary CRCs were evaluated immunohistochemically for PBK expression to assess its ability as a prognostic factor. CRC tumor cells variably expressed PBK (range, 0–100%; median, 32%) in the nucleus and cytoplasm. Univariate analyses identified a significant inverse correlation between PBK expression and pT stage (
P
<0.0001). Furthermore, patients carrying CRC with higher PBK expression showed significantly favorable survival (
P
=0.0094). Multivariate Cox proportional hazards regression analysis revealed high PBK expression (HR, 0.52;
P
=0.015) as one of the potential favorable factors for CRC patients. PBK expression showed significant correlation to Ki-67 labeling indices (
ρ
=0.488,
P
<0.0001). In vitro, the PBK inhibitor OTS514 suppressed cellular proliferation of CRC cells with PBK expression through downregulation of P-ERK and induction of apoptosis. These results suggest that PBK-targeting therapeutics may be useful for the treatment of PBK-expressing CRC patients.
A need exists for seeking effective treatments for castration-resistant prostate cancer (CRPC) in response to its emergence following androgen deprivation therapy as a major clinical problem. In the ...present study, we investigated the chemopreventive and chemotherapeutic potential of luteolin, a flavonoid with antioxidative properties, on prostate cancer, including CRPC. Luteolin inhibited the progression of rat prostate carcinogenesis by induction of apoptosis in a transgenic rat for adenocarcinoma of prostate (TRAP) model. Luteolin decreased cell proliferation in a dose-dependent manner and induced apoptosis with the activation of caspases 3 and 7 in both rat (PCai1, established from a TRAP prostate tumor) and human (22Rv1) CRPC cells. Dietary luteolin also suppressed tumor growth via an increase in apoptosis and inhibition of angiogenesis in PCai1 and 22Rv1 xenografts implanted in castrated nude mice. We also focused on androgen receptor splice variant 7 (AR-V7), which contributes to cell proliferation and therapeutic resistance in CRPC. Luteolin dramatically suppressed AR-V7 protein expression in 22Rv1 cells in vitro and ex vivo. Microarray analysis identified MiR-8080, which contains a possible target sequence for AR-V7 3'-UTR, as a gene upregulated by luteolin. MiR-8080 transfection decreased the AR-V7 expression level and the induction of apoptosis in 22Rv1 cells. Furthermore, miR-8080 knockdown canceled luteolin decreasing AR-V7 and the cell growth of 22Rv1. MiR-8080 induced by luteolin intake enhanced the therapeutic effect of enzalutamide on 22Rv1 xenografts under castration conditions. These results indicate luteolin inhibits CRPC by AR-V7 suppression through miR-8080, highlighting luteolin and miR-8080 as promising therapeutic agents for this disease.
Diffuse malignant mesothelioma of the pleura is a highly aggressive tumor typically associated with short survival. ALCAM (CD166), a type I transmembrane protein, is a member of the immunoglobulin ...superfamily. In normal cells, ALCAM regulates physiological processes such as angiogenesis and immune response. In cancer, it is associated with neoplastic progression, including invasion, migration, and metastasis. Furthermore, ALCAM is considered one of the cancer stem cell markers such as ALDH1 (ALDH1A1) and SALL4. The PD-L1 (CD274)/PD-1 (PDCD1, CD279) pathway is crucial for the modulation of immune responses in normal cells. Nevertheless, pathologic activation of the PD-L1/PD-1 pathway participates in immune evasion by tumor cells. Many PD-L1–expressing tumor cells have been identified in different types of cancer, including malignant mesothelioma. In this study, 175 well-characterized primary diffuse pleural mesotheliomas, including the epithelioid (n = 148), biphasic (n = 15), and sarcomatoid (n = 12) histotypes, were evaluated immunohistochemically for cancer stem cell markers (ALCAM, ALDH1, and SALL4) and PD-L1 expression. Twenty-five percent of the mesotheliomas (43/175) expressed ALCAM, whereas ALDH1 and SALL4 positivity was seen in 1% to 2% of cases. Thirty-three percent of the analyzed tumors (57/175) contained PD-L1–positive cells. Overall survival was significantly decreased in the cohort of patients with ALCAM- or PD-L1–positive tumors (both P < .01). Furthermore, the multivariate Cox hazards regression analysis identified ALCAM and PD-L1 (both P < 0.01) as potential independent risk factors. Thus, a combination of these 2 markers might be useful for prognostication and planning the treatment of patients with malignant pleural mesothelioma.
•PD-L1 and stem cell marker expressions were analyzed in malignant mesotheliomas.•PD-L1 and ALCAM were expressed in 33% and 25% of mesothelioma cases, respectively.•The Cox proportional hazards model identified these proteins as independent risk factors for death.
p53 immunohistochemistry is considered an accurate surrogate marker reflecting the underlying TP53 mutation status and has utility in tumor diagnostics. In the present study, 269 primary CRCs were ...immunohistochemically evaluated for p53 expression to assess its utility in diagnostic pathology and prognostication. p53 expression was wild-type in 59 cases (23%), overexpressed in 143 cases (55%), completely lost in 50 cases (19%), and cytoplasmic in 10 cases (4%). p53 immunoreactivity was associated with tumor size (p = 0.0056), mucus production (p = 0.0015), and mismatch repair (MMR) system status (p < 0.0001). Furthermore, among CRCs with wild-type p53 expression, a significantly higher number of cases had decreased CDX2 than those with p53 overexpression (p = 0.012) or complete p53 loss (p = 0.043). In contrast, among CRCs with p53 overexpression, there were significantly fewer ALCAM-positive cases than p53 wild-type cases (p = 0.0045). However, no significant association was detected between p53 immunoreactivity and the “stem-like” immunophenotype defined by CDX2 downregulation and ALCAM-positivity. Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio HR = 0.17, p < 0.0001), younger age (HR = 0.52, p = 0.021), and female sex (HR = 0.55, p = 0.046) as potential favorable factors. The analysis also revealed complete p53 loss (HR = 2.16, p = 0.0087), incomplete resection (HR = 2.65, p = 0.0068), and peritoneal metastasis (HR = 5.32, p < 0.0001) as potential independent risk factors for patients with CRC. The sub-cohort survival analyses classified according to chemotherapy after surgery revealed that CRC patients with wild-type p53 expression tended to have better survival than those with overexpression or complete loss after chemotherapy. Thus, immunohistochemistry for p53 could be used for the prognostication and chemotherapy target selection of patients with CRC.
Activity of GLI transcription factors of Hedgehog signaling is key for various cancer cell properties, especially in pancreatic ductal adenocarcinoma (PDAC). Zinc-finger transcriptional regulators ...ZIC1 to ZIC5 of ZIC gene family were demonstrated to associate with GLI to increase the nuclear accumulation and transcriptional activity of GLI. Notwithstanding this supportive role for GLI-dependent transcription, it was not fully understood whether ZIC plays an independent role in cancer cell biology. Here, we found that ZIC2 is indispensable in the regulation of PDAC cell apoptosis. We found that human PDAC cell lines uniquely express ZIC2. ZIC2 knockdown induced PDAC cell apoptosis; conversely, ZIC2 over-expression enhanced the cellular proliferation. Through a comprehensive screening, we identified fibroblast growth factor receptor 3 (FGFR3) and ANNEXIN A8 (ANXA8) as genes up-regulated by ZIC2 in PDAC cells. The forced expression of these two genes cooperatively rescued the apoptosis of ZIC2-knockdown cells. Immunohistochemical analyses further supported the correlation of ZIC2 expression and these genes in human pancreata harboring PDAC. Intriguingly, the ZIC2-mediated up-regulation of FGFR3 and ANXA8 was indicated to be GLI -independent. This evidence highlights the indispensable role of ZIC2 in regulating cellular proliferation and apoptosis during PDAC development and suggests a potential therapeutic target for PDAC.
The up-regulation of chemokine receptors CXCR4 and CXCR7 impacts on the distant metastasis and prognosis of breast cancer, though knowledge about the regulatory mechanism of their expressions is ...limited. Meanwhile, the GLI transcription factors of Hedgehog signaling have been reported to play a pivotal role in the development and progression of many types of human cancer. In breast cancer, the increased expression of GLI1 correlated with metastasis and unfavorable overall prognosis, though its molecular mechanism is also not fully understood. Based on our findings that GLI1 enhanced the lung metastasis of breast cancer cells in a mouse model system, we comprehensively screened for genes up-regulated by GLI1 in breast cancer cells, and as such identified CXCR4, CXCR7/ACKR3, and actin-binding protein LCP1/L-PLASTIN, all of which have been reported to be involved in CXCL12-stimulating signaling. In breast cancer cells, we found that GLI1 and GLI2 up-regulated these expressions, while treatment with GLI-specific inhibitor GANT61 reduced the expressions. As for CXCR4, we confirmed it as a direct target of GLI1 through the reporter assay and the chromatin immunoprecipitation assay. We also found that GLI1 enhanced CXCL12-induced ERK phosphorylation and cell migration, both of which were blocked by either CXCR4-specific inhibitor or knockdown of CXCR7 or LCP1. These evidences suggest an indispensable role of GLI1 in the migration and metastasis of breast cancer cells through CXCL12/CXCR4 signaling enhancement.
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