Liver metastasis is a leading cause of death in patients with colorectal cancer. We previously found that colorectal cancer tumor-initiating cells (TICs) expressing CD110, the thrombopoietin ...(TPO)-binding receptor, mediate liver metastasis. Here, we show that TPO promotes metastasis of CD110+ TICs to the liver by activating lysine degradation. Lysine catabolism generates acetyl-CoA, which is used in p300-dependent LRP6 acetylation. This triggers tyrosine phosphorylation of LRP6, ultimately activating Wnt signaling to promote self-renewal of CD110+ TICs. Lysine catabolism also generates glutamate, which modulates the redox status of CD110+ TICs to promote liver colonization and drug resistance. Mechanistically, TPO-mediated induction of c-myc orchestrates recruitment of chromatin modifiers to regulate metabolic gene expression. Our findings, therefore, establish TPO as a component of the physiological environment critical for metastasis of colorectal cancer to the liver.
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•Colorectal CD110+ cancer cells in liver metastases show enhanced lysine degradation•TPO-mediated activation of lysine degradation is required for liver metastasis•Lysine catabolism leads to activated Wnt signaling and a shift in redox status•TPO-induced c-myc recruits chromatin modifiers to regulate gene expression
Liver metastasis is a leading cause of death for colorectal cancer patients. In this study, Wu et al. show that metabolic reprogramming in colorectal cancer tumor-initiating cells to enhance lysine metabolism is a key step in this process and is mediated by the soluble environmental factor thrombopoietin.
Background
Laparoscopic incisional and ventral hernia repair (LIVHR) is an alternative approach to conventional open incisional and ventral hernia repair (OIVHR). A consensus on outcomes of LIVHR ...when compared with OIVHR has not been reached.
Methods
As the basis for the present study, we performed a systematic review and meta-analysis of all randomized controlled trials comparing LIVHR and OIVHR.
Results
Eleven studies involving 1,003 patients were enrolled. The incidences of wound infection were significantly lower in the laparoscopic group than that in the open group (laparoscopic group 2.8 %, open group 16.2 %; RR = 0.19, 95 % CI 0.11–0.32;
P
< 0.00001). The rates of wound drainage were significantly lower in the laparoscopic group than that in the open group (laparoscopic group 2.6 %, open group 67.0 %; RR = 0.06, 95 % CI 0.03–0.09;
P
< 0.00001). However, the rates of bowel injury were significantly higher in the laparoscopic group than in the open group (laparoscopic group 4.3 %, open group 0.81 %; RR = 3.68, 95 % CI 1.56–8.67;
P
= 0.003). There were no significant differences between the two groups in the incidences of hernia recurrence, postoperative seroma, hematoma, bowel obstruction, bleeding, and reoperation. Descriptive analyses showed a shorter length of hospital stay in the laparoscopic group.
Conclusions
Laparoscopic incisional and ventral hernia repair is a feasible and effective alternative to the open technique. It is associated with lower incidences of wound infection and shorter length of hospital stay. However, caution is required because it is associated with an increased risk of bowel injury compared with the open technique. Given the relatively short follow-up duration of trials included in the systematic review, trials with long-term follow-up are needed to compare the durability of laparoscopic and open repair.
Although mRNA vaccines have been effective against multiple cancers, their efficacy against stomach adenocarcinoma (STAD) remains undefined. Immunotyping can indicate the comprehensive immune status ...in tumors and their immune microenvironment, which is closely associated with therapeutic response and vaccination potential. The aim of this study was to identify potential antigens in STAD for mRNA vaccine development, and further distinguish immune subtypes of STAD to construct an immune landscape for selecting suitable patients for vaccination.
The gene expression and clinicopathological features of patients with gastric cancer were downloaded from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression Program (GTEx). 729 samples from GSE66229 and GSE84437 were downloaded through GEO and were used as the validation cohorts. Differential gene expression, genetic alterations and prognosis were analyzed using the R package, cBioPortal program and Kaplan-Meier. The relationship between tumor antigens and immune cells was evaluated and plotted by TIMER. ConsensusClusterPlus was used for consistency matrix construction and data clustering, and graph learning-based dimensional reduction was used to depict immune landscape. WGCNA was used to estimate the relationship between the color modules and immune subtypes.
Two overexpressed and mutated tumor antigens associated with poor prognosis and infiltration of antigen presenting cells were identified in STAD, including RAI14 and NREP. The immune subtypes showed distinct molecular, cellular and clinical characteristics. IS1 and IS2 exhibited immune-activated phenotypes and correlated to better survival compared to IS3, while IS3 tumors was immunologically cold. Immunogenic cell death modulators, immune checkpoints, and CA125, and CEA were also differentially expressed among the three immune subtypes. Finally, the immune landscape of STAD showed a high degree of heterogeneity between individual patients.
RAI14 and NREP are potential antigens for developing anti-STAD mRNA vaccine, and patients with IS1 and IS3 tumors may be suitable for vaccination.
Automated vehicles (AVs) are not yet widely accepted by the public, and the COVID-19 pandemic has the potential to lead to a shift in attitudes toward travel modes and vehicles because of travel ...restrictions and the risk of viral transmission. Therefore, it is necessary to understand how AVs are being accepted by the public during the pandemic. This study investigated public acceptance of AVs across two periods of the COVID-19 epidemic prevention and control in China via 19-question online surveys, including the travel modes, AVs acceptance, and sociodemographic. A total of 429 responses were collected. Results showed that the public acceptance of AVs was on the positive side, but was diverse in items: the average extra cost willing to pay for a fully AV was 28,855.88 CNY (4116.39 USD), and 26.8% of respondents were not willing to pay for it. Respondents agreed on the benefits of AVs and are concerned about legal liability for drivers and fuel economy, and had a positive attitude of commercial AVs. Most acceptance items had differences between the pandemic periods, indicating that people were more willing to accept AVs during period with higher risk of infection. However, only the difference in perceived benefits of AV of ensuring social distance was statistically significant. Gender, age, and ownership of vehicle had greater effects on AVs acceptance, while driving ability and driving experience had small effects on it. This survey can provide insights for studies examining the acceptance of AVs across time, and exploring factors influencing AVs acceptance.
Human tumors harbor a plethora of microbiota. It has been shown that the composition and diversity of intratumor microbiome are significantly associated with the survival of patients with pancreatic ...ductal adenocarcinoma (PDAC). However, the association in Chinese patients as well as the effect of different microorganisms on inhibiting tumor growth are unclear. In this study, we collected tumor samples resected from long-term and short-term PDAC survivors and performed 16S rRNA amplicon sequencing. We found that the microbiome in samples with different survival time were significantly different, and the differential bacterial composition was associated with the metabolic pathways in the tumor microenvironment. Furthermore, administration of
, one of the differential bacteria, induced a better tumor growth inhibition effect when combined with the immune checkpoint inhibitor anti-programmed cell death-1 (anti-PD-1) treatment in mice bearing 4T1 tumor. These results indicate that specific intratumor microbiome can enhance the anti-tumor effect in the host, laying a foundation for further clarifying the underlying detailed mechanism.
Background
Cancer stem cells (CSCs) are believed to form metastases. We sought to determine whether CD70 + subpopulation in human breast cancers represents the CSCs accounting for distant metastasis.
...Methods
We measured the expression levels of CD70 in breast cancer cell lines and 122 primary breast cancer samples. We characterized the functional roles of CD70 + subpopulation in distant metastasis of breast cancers.
Results
We observed a distinct pattern of CD70 expression in a panel of primary breast carcinoma samples, indicating that CD70 serves as a biomarker of lung-specific metastasis. CD70− and CD70+ cell populations isolated from breast cancer cell lines exhibited epithelial and mesenchymal phenotypes, respectively. CD70+ cells, but not CD70− cells, possessed self-renewal and differentiation potentials. Tumorsphere formation in suspension cultures and in vivo tumorigenicity were significantly greater in CD70+ cells than in CD70− cells. Furthermore, the development of lung metastases induced by orthotopic injection was markedly increased in mice inoculated with CD70 + cells. CD70 contributed to the promotion of lung metastases by enhancing self-renewal potential of CD70 + cells.
Conclusions
We isolated CSCs from primary human breast cancers and found that CD70 + subpopulations mediate lung-specific metastasis. These findings might be used to aid in selection of patients for postoperative adjuvant therapy.
Negative lymph node (NLN) count has been reported to provide more accurate prognostic information than the N stage alone in patients with rectal cancer (RC). Since preoperative radiotherapy (Pre-RT) ...can significantly affect the LN status, it is unclear whether NLN count still has prognostic value count on survival of patients with RC who received Pre-RT.
In this study, clinicopathological characteristics, number of positive LNs and survival time were collected from Surveillance, Epidemiology, and End Results Program (SEER)-registered RC patients. Univariate and multivariate Cox proportional hazards models were used to assess the risk factors for survival.
X-tile plots identified 9 (P < 0.001) as the optimal cutoff NLN value to divide the patients into high and low risk subsets in terms of cause specific survival (CSS). NLN count was validated as independently prognostic factor in univariate and multivariate analysis (P < 0.001). Subgroup analysis showed that NLN count was an independently prognostic factor for patients with stage ypII (P = 0.002) and ypIII (P < 0.001).
Our results firmly demonstrated that NLN count provides accurate prognostic information for RC patients with Pre-RT.
A major obstacle for successful management of patients with colorectal carcinoma (CRC) is resistance to anti-cancer cytotoxic treatments. Here, we identified a mechanism of multidrug resistance in ...wild-type Kras CRCs based on the survival of a cell subpopulation characterized by Sirt5 expression. Sirt5+ cells in wild-type Kras CRCs are resistant to either chemotherapeutic agents or cetuximab and serve as a reservoir for recurrence. Sirt5 demalonylates and inactivates succinate dehydrogenase complex subunit A (SDHA), leading to an accumulation of the oncometabolite succinate. Succinate binds to and activates a reactive oxygen species-scavenging enzyme, thioredoxin reductase 2 (TrxR2), to confer chemotherapy resistance. In contrast, Sirt5+ cells exhibit an elevated succinate-to-aKG ratio that inhibits aKG-dependent dioxygenases to maintain cetuximab resistance. Our findings suggest that Sirt5 inhibitors in combination with chemotherapeutic agents and/or cetuximab may represent a therapeutic strategy for CRC patients harboring wild-type Kras.
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•Sirt5+ subset in wild-type Kras colorectal tumors determines multidrug resistance•Sirt5-mediated demalonylation and inactivation of SDHA lead to succinate accumulation•Succinate binds to and activates TrxR2 to maintain chemotherapy resistance•Succinate inhibits aKG-dependent dioxygenases to regulate cetuximab resistance
Du et al. show that a Sirt5+ subpopulation represents a critical driving force behind the development of multidrug resistance in wild-type Kras colorectal carcinomas and that Sirt5-mediated SDHA inactivation has implications for this process.
Recurrent tumors originate from cancer stem cells (CSCs) that survive conventional treatments. CSCs consist of heterogeneous subpopulations that display distinct sensitivity to anticancer drugs. Such ...a heterogeneity presents a significant challenge in preventing tumor recurrence. In the current study, we observed that quiescent CUB-domain-containing protein 1 (CDCP1)+ CSCs are enriched after chemotherapy in mutant Kirsten rat sarcoma viral oncogene homolog (Kras) colorectal carcinomas (CRCs) and serve as a reservoir for recurrence. Mechanistically, glucose catabolism in CDCP1+ CSCs is routed to the oxidative pentose phosphate pathway (PPP); multiple cycling of carbon backbones in the oxidative PPP potentially maximizes NADPH reduction to counteract chemotherapy-induced reactive oxygen species (ROS) formation, thereby allowing CDCP1+ CSCs to survive chemotherapeutic attack. This is dependent on silent mating type information regulation 2 homolog 5 (Sirt5)-mediated inhibition of the glycolytic enzyme triosephosphate isomerase (TPI) through demalonylation of Lys56. Blocking demalonylation of TPI at Lys56 increases chemosensitivity of CDCP1+ CSCSs and delays recurrence of mutant Kras CRCs in vivo. These findings pinpoint a new therapeutic approach for combating mutant Kras CRCs.
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