Treatment strategy for HER2-negative advanced gastric cancer: salvage-line strategy for advanced gastric cancer.

After immune checkpoint inhibitor (ICI) comes into third-line treatment of advanced gastric cancer, the therapeutic strategy has been dramatically changed. Recent first-line regimen, which consists of ICI and chemotherapeutic agents, prolonged progression-free survival, and subsequent treatment options enabled continuous treatment beyond second-line therapy. Moreover, the advent of vascular endothelial growth factor (VEGF)-targeted agents including angiogenesis inhibitors and TKIs provides an opportunity of considering the interaction between ICI and anti-VEGF agents, and facilitating novel treatment proposal. Although clinical benefit of prolonged VEGF blockade after disease progression has not been confirmed in gastric cancer, combination therapy of cytotoxic agents and anti-VEGF agent, such as irinotecan plus ramucirumab demonstrated favorable objective response rate and progression-free survival in third- or later-line setting. In this review, we discuss recent progress and future directions of later-line treatments of HER2-negative advancer gastric cancer.

Dabrafenib and trametinib administration in patients with BRAF V600E/R or non-V600 BRAF mutated advanced solid tumours (BELIEVE, NCCH1901): a multicentre, open-label, and single-arm phase II trial.

Background: BRAF V600 mutations are common in melanoma, thyroid, and non-small-cell lung cancers. Despite dabrafenib and trametinib being standard treatments for certain cancers, their efficacy across various solid tumours remains unelucidated. The BELIEVE trial assessed the efficacy of dabrafenib and trametinib in solid tumours with BRAF V600E/R or non-V600 BRAF mutations. Methods: Between October 1, 2019, and June 2022, at least 50 patients with measurable and seven without measurable diseases examined were enrolled in a subcohort of the BELIEVE trial (NCCH1901, jRCTs031190104). BRAF mutated solid tumour cases other than BRAF V600E mutated colorectal cancer, melanoma, and non-small cell lung cancer cases were included. Patients with solid tumours received dabrafenib (150 mg) twice daily and trametinib (2 mg) once daily until disease progression or intolerable toxicity was observed. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). Bayesian analysis was performed using a prior distribution with a 30% expected response rate [Beta (0.6, 1.4)]. Findings: Fourty-seven patients with measurable disease, mainly with the BRAF V600E mutation (94%), and three others with non-V600E BRAF mutations (V600R, G466A, and N486_P490del) were enrolled. The primary sites included the thyroid gland, central nervous system, liver, bile ducts, colorectum, and pancreas. The confirmed ORR was 28.0%; the expected value of posterior distribution [Beta (14.6, 37.4)] was 28.1%, although the primary endpoint was achieved, not exceeding an unexpectedly high response rate of 60% obtained using Bayesian analysis. The disease control rate (DCR) was 84.0%. The median PFS was 6.5 months (95% confidence interval [CI]; 4.2-7.2 months, 87.8% at 6 months). Responses were observed across seven tumour types. Median OS was 9.7 months (95% CI, 7.5-12.2 months). Additional patients without measurable diseases had a median PFS of 4.5 months. Adverse events (AEs) were consistent with previous reports, with 45.6% of patients experiencing grade ≥3 AEs. Interpretation: This study reported promising efficacy against BRAF V600-mutant tumours. Dabrafenib and trametinib would offer a new therapeutic option for rare cancers, such as high-grade gliomas, biliary tract cancer, and thyroid cancer. Funding: This study was funded by the Japan Agency for Medical Research and Development (22ck0106622h0003) and a Health and Labour Sciences Research Grant (19EA1008).

Early detection of brain metastases and appropriate local therapy followed by systemic chemotherapy may improve the prognosis of gastric cancer.

Brain metastases develop in 0.5-0.7% of patients with gastric/gastroesophageal junction (G/GEJ) cancer. Although rare, brain metastasis is often identified when the patient is already symptomatic; hence prognosis is poor. Given the therapeutic developments for G/GEJ cancer, overall survival is prolonged, thereby the incidence of brain metastases is predicted to increase. We retrospectively surveyed the rate of brain metastasis among 1257 patients diagnosed with G/GEJ cancer who received chemotherapy between January 2011 and April 2021. We investigated the time of onset of brain metastasis, treatments administered, and impact of the metastasis on the overall treatment course and prognosis. Of the 741 patients included in the analysis, brain metastasis was confirmed in 16 (2.2%). The median survival time (MST) from G/GEJ cancer diagnosis was 14.9 months in patients with brain metastasis detected during the treatment period, and the MST from the diagnosis of brain metastasis was 2.8 months. Patients who received chemotherapy exhibited prolonged survival compared with those who did not (12.4 months vs 1.0 months, p < 0.001). Our findings suggest that the early detection of brain metastases and local therapy for poor responders to chemotherapy enable the continuation of chemotherapy and prolong survival.

Long noncoding RNA 01534 maintains cancer stemness by downregulating endoplasmic reticulum stress response in colorectal cancer.

Background: Studies have shown that cancer stemness and the endoplasmic reticulum (ER) stress response are inversely regulated in colorectal cancer (CRC), but the mechanism has not been fully clarified. Long noncoding RNAs (lncRNAs) play key roles in cancer progression and metastasis. In this study we investigated lncRNA 01534 (LINC01534) as a possible modulator between cancer stemness and ER stress response. Methods: In vitro experiments using CRC cell lines were performed to explore a possible role of LINC01534. The expression of LINC01534 in clinical CRC samples was assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and in situ hybridization. Results: Silencing LINC01534 led to suppression of cell proliferation, invasiveness, and cell cycle progression at the G2-M phase, and promoted apoptosis. Moreover, we found that silencing LINC01534 suppressed cancer stemness, while it activated the ER stress response, especially through the PERK/eIF2α signaling pathway. In situ hybridization revealed LINC01534 was expressed in tumor cells and upregulated in CRC tissues compared with normal epithelium. A survival survey indicated that high LINC01534 expression was significantly associated with shorter overall survival in 187 CRC patients. Conclusion: This is the first report on LINC01534 in human cancer. Our findings suggest that LINC01534 may be an important modulator of the maintenance of cancer stemness and suppression of the ER stress response, and that it could be a novel prognostic factor in CRC.

Clinical outcomes of neoadjuvant chemotherapy for resectable colorectal liver metastasis with intermediate risk of postoperative recurrence: A multi-institutional retrospective study.

Aims: Risk-scoring systems for colorectal liver metastasis (CRLM) after hepatectomy allow prognoses to be predicted preoperatively. We investigated the clinical outcomes of neoadjuvant chemotherapy for resectable CRLM according to patient risk status, aiming to determine the subgroup of patients who could benefit from neoadjuvant chemotherapy. Methods: In this multi-institutional retrospective analysis, the preoperative risk score was calculated from six previously reported factors: synchronous metastases, primary lymph node positivity, tumor number, largest tumor diameter, extrahepatic metastasis, and the preoperative carbohydrate antigen 19-9 level. Patients were divided into three groups according to their risk scores: low risk (score = 0), intermediate risk (score 1-10), and high risk (score ≥11). Overall and recurrence-free survival curves were calculated using the Kaplan-Meier method. After propensity-score matching in the intermediate-risk group, we compared clinicopathological features and outcomes. Results: There were 318 cases, from 20 institutions. The preoperative risk score could be calculated in 277 cases. There were 34, 192, and 51 patients in the low-, intermediate-, and high-risk groups, respectively. Intermediate-risk group patients who received neoadjuvant chemotherapy had significantly better recurrence-free survival than that of patients without neoadjuvant chemotherapy (P = .0453). After propensity-score matching in the intermediate-risk group, the recurrence-free survival rate was better in patients who received neoadjuvant chemotherapy (P = .0261). But the overall survival rate was not improved after the matching. Conclusion: Neoadjuvant chemotherapy for resectable CRLM might prolong the recurrence-free survival period for intermediate-risk patients with preoperative risk scores in the range of 1-10, but the overall survival was not improved by neoadjuvant chemotherapy.

Comprehensive profiling of novel epithelial-mesenchymal transition mediators and their clinical significance in colorectal cancer.

Epithelial-mesenchymal transition (EMT) is a drastic phenotypic change during cancer metastasis and is one of the most important hallmarks of aggressive cancer. Although the overexpression of some specific transcription factors explains the functional alteration of EMT-induced cells, a complete picture of this biological process is yet to be elucidated. To comprehensively profile EMT-related genes in colorectal cancer, we quantified the EMT induction ability of each gene according to its similarity to the cancer stromal gene signature and termed it "mesenchymal score." This bioinformatic approach successfully identified 90 candidate EMT mediators, which are strongly predictive of survival in clinical samples. Among these candidates, we discovered that the neuronal gene ARC, possibly originating from the retrotransposon, unexpectedly plays a crucial role in EMT induction. Profiling of novel EMT mediators we demonstrated here may help understand the complexity of the EMT program and open up new avenues for therapeutic intervention in colorectal cancer.

Specific activation of glycolytic enzyme enolase 2 in BRAF V600E-mutated colorectal cancer.

The BRAF V600E mutation occurs in approximately 10% of patients with metastatic colorectal cancer (CRC) and constitutes a distinct subtype of the disease with extremely poor prognosis. To address this refractory disease, we investigated the unique metabolic gene profile of BRAF V600E-mutated tumors via in silico analysis using a large-scale clinical database. We found that BRAF V600E-mutated tumors exhibited a specific metabolic gene expression signature, including some genes that are associated with poor prognosis in CRC. We discovered that BRAF V600E-mutated tumors expressed high levels of glycolytic enzyme enolase 2 (ENO2), which is mainly expressed in neuronal tissues under physiological conditions. In vitro experiments using CRC cells demonstrated that BRAF V600E-mutated cells exhibited enhanced dependency on ENO2 compared to BRAF wild-type cancer cells and that knockdown of ENO2 led to the inhibition of proliferation and migration of BRAF V600E-mutated cancer cells. Moreover, inhibition of ENO2 resulted in enhanced sensitivity to vemurafenib, a selective inhibitor of BRAF V600E. We identified AP-1 transcription factor subunit (FOSL1) as being involved in the transcription of ENO2 in CRC cells. In addition, both MAPK and PI3K/Akt signaling were suppressed upon inhibition of ENO2, implying an additional oncogenic role of ENO2. These results suggest the crucial role of ENO2 in the progression of BRAF V600E-mutated CRC and indicate the therapeutic implications of targeting this gene.

Impact of sarcopenia in patients with advanced or recurrent colorectal cancer treated with regorafenib.

BACKGROUND: Regorafenib is a key agent for patients with advanced or recurrent colorectal cancer. Sarcopenia represented by skeletal muscle depletion is closely related to frailty and predicts oncological prognoses. We hypothesized that sarcopenia negatively affects the time to treatment failure (TTF) or overall survival (OS) of patients treated with regorafenib. METHODS: We retrospectively reviewed the medical records of all patients treated with regorafenib between May 2013 and April 2019 at our institution. The cross-sectional area of the psoas muscle at the level of the third lumbar vertebra on baseline computed tomography (CT) was assessed to calculate the psoas muscle index (PMI). Sarcopenia was defined based on PMI cut-off values for Asian adults (6.36 cm2/m2 for males and 3.92 cm2/m2 for females). RESULTS: Thirty-four patients were analyzed. The prevalence of sarcopenia was 44.1%. Sarcopenia was significantly associated with poorer OS (median 3.2 vs. 5.3 months, p = 0.031). Less 75% 1-Month Relative Dose Intensity patients experienced significantly shorter TTF and OS than the rest, as did patients receiving total regorafenib dose of < 3360 mg (median 3.1 and 9.4 months, p < 0.001). Multivariate analysis showed that sarcopenia was a significant predictor of prognosis. CONCLUSION: Sarcopenia was a predictive marker of negative outcome for patients with advanced or recurrent colorectal cancer treated with regorafenib. Screening for sarcopenia can be used to identify patients more likely to benefit from regorafenib in routine clinical practice.

Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies.

Comprehensive genomic profiling enables genomic biomarker detection in advanced solid tumors. Here, to evaluate the utility of circulating tumor DNA (ctDNA) genotyping, we compare trial enrollment using ctDNA sequencing in 1,687 patients with advanced gastrointestinal (GI) cancer in SCRUM-Japan GOZILA (no. UMIN000016343), an observational ctDNA-based screening study, to enrollment using tumor tissue sequencing in the same centers and network (GI-SCREEN, 5,621 patients). ctDNA genotyping significantly shortened the screening duration (11 versus 33 days, P < 0.0001) and improved the trial enrollment rate (9.5 versus 4.1%, P < 0.0001) without compromising treatment efficacy compared to tissue genotyping. We also describe the clonal architecture of ctDNA profiles in ~2,000 patients with advanced GI cancer, which reinforces the relevance of many targetable oncogenic drivers and highlights multiple new drivers as candidates for clinical development. ctDNA genotyping has the potential to accelerate innovation in precision medicine and its delivery to individual patients.

Combination Therapy With S-1, Oxaliplatin and Leucovorin in Patients With Advanced Esophageal Squamous Cell Carcinoma.

BACKGROUND/AIM: In this study, we assessed the safety and efficacy of combination therapy with S-1, oxaliplatin and leucovorin (SOL) in advanced esophageal squamous cell carcinoma (ESCC) patients. PATIENTS AND METHODS: Ten unresectable or recurrence ESCC patients, who had been previously treated with more than two regimens were included in this study. The treatment schedule comprised S-1 40-60 mg and fixed dose of leucovorin 25 mg together orally twice a day for one week, followed by one-week of rest. Oxaliplatin 85 mg/m2 was given as an intravenous infusion on day one, repeated every two weeks. RESULTS: Of the eight patients with measurable lesions, two patients with partial response (25%) and two with stable disease (25%) were observed. Disease control rate was 50%. Median progression-free survival and overall survival were 5.0 and 9.3 months, respectively. The main common adverse events were malaise (60%), decreased appetite (50%), peripheral sensory neuropathy (40%). CONCLUSION: SOL therapy showed promising antitumor activity with acceptable toxicity even for heavily pretreated ESCC.

Gallbladder cancer harboring ERBB2 mutation on the primary and metastatic site: A case report.

BACKGROUND: Bile duct cancer constitutes gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (ICA), and extrahepatic cholangiocarcinoma (ECA). These three entities show morphological and immunohistochemical resemblance so that it is difficult to differentiate between primary ICA and liver metastasis of GBC, which sometimes becomes a point of discussion in clinical practice. Although these cancers demonstrate significant differences in their mutational landscape, several reports demonstrated shared genomic alteration in paired primary and metastatic site aids in distinguishing metastatic recurrence from second primary cancers. CASE SUMMARY: We present a 73-year-old female patient who underwent curative resection for GBC harboring epidermal growth factor receptor 2 (ERBB2) activating mutation on next-generation sequencing (NGS)-based genomic testing. One year later, a hepatic lesion was observed on follow-up imaging and she underwent surgical resection for a pathological diagnosis. The histological findings of the hepatic lesion were similar to those of the primary lesion. Additionally, using NGS panel testing, the hepatic lesion was found to have ERBB2 activating mutation, which is the identical mutation detected in the sequencing result of the primary site. ERBB2 activating mutation occurs more frequently in GBC than ICA and ECA. Therefore, in the present case, we think this molecular finding potentiated the diagnosis of the liver mass toward a metastatic recurrence. Additionally, this patient underwent HER2-targeted treatment with lapatinib in combination with capecitabin and obtained clinical benefit. CONCLUSION: This case illustrated NGS panel usefulness in distinguishing GBC recurrence from second primary cancer and HER2-targeted agent efficacy on ERBB2 mutated GBC.

Dysphagia Score as a Predictor of Adverse Events Due to Triplet Chemotherapy and Oncological Outcomes in 434 Consecutive Patients with Esophageal Cancer.

BACKGROUND: Dysphagia is a major symptom of esophageal cancer (EC) that significantly affects patient quality of life; however, little is known regarding its clinical impact on the treatment course in patients with EC. METHODS: This retrospective study included 434 consecutive patients with EC who received docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy as an initial treatment. We evaluated the relationships between the dysphagia score at diagnosis and clinicopathological factors, including DCF therapy-related adverse events, tumor response, and survival. RESULTS: The dysphagia scores were 0 in 208 patients (47.9%), 1 in 82 patients (18.9%), 2 in 52 patients (12.0%), 3 in 59 patients (13.6%), and 4 in 33 patients (7.6%). High (≥ 3) dysphagia scores were significantly associated with high incidences of grade 3/4 febrile neutropenia (FN) (79.3 vs. 35.7%, P < 0.001) and diarrhea (63.0 vs. 28.1%, P < 0.001) compared with low (≤ 2) scores. Logistic regression analysis further identified the dysphagia scores as an independent predictor of both FN and severe diarrhea during DCF chemotherapy. Furthermore, compared with low scores, high dysphagia scores were associated with a worse clinical response to chemotherapy (response rate 65.2 vs. 78.7%, P = 0.008) and worse 5-year overall survival (35.4 vs. 56.4%, P = 0.001). CONCLUSIONS: The dysphagia score at diagnosis was an independent predictor of FN and severe diarrhea. Furthermore, this score might be useful in predicting chemotherapy response and long-term survival in patients treated with DCF.

Nivolumab-induced interstitial lung disease in a patient with gastric cancer.

We herein report a case of nivolumab-induced interstitial lung disease in a patient with gastric cancer. Nivolumab is a fully human IgG4 monoclonal antibody inhibitor of programmed death-1. A 69-year-old woman with metastatic gastric cancer being treated with nivolumab as fifth-line therapy developed interstitial pneumonia 27 months after starting treatment with nivolumab. Chest computed tomography demonstrated a cryptogenic organizing pneumonia pattern in both lung lobes. This was thought as an immune-related adverse event (irAEs), but stopping the administration of nivolumab failed to resolve the presence of lung shadows. Treatment with steroid pulse therapy twice and subsequently with prednisolone gradually improved the pulmonary function. The administration of high-dose corticosteroid is recommended after the diagnosis of irAEs in nivolumab treatment. Since recovering from pulmonary dysfunction, the patient remains alive with no disease progression. The immediate diagnosis and treatment of irAEs are crucial for achieving a good outcome.

Disruption of Endolysosomal RAB5/7 Efficiently Eliminates Colorectal Cancer Stem Cells.

Given that cancer stem cells (CSC) play a key role in drug resistance and relapse, targeting CSCs remains promising in cancer therapy. Here we show that RAB5/7, which are involved in the endolysosomal pathway, play key roles in the maintenance of CSC survival via regulation of the mitophagic pathway. Inhibition of RAB5/7 efficiently eliminated colorectal CSCs and disrupted cancer foci. In addition, we identified mefloquine hydrochloride, an antimalarial drug, as a novel RAB5/7 inhibitor and promising colorectal CSC-targeting drug. Endolysosomal RAB5/7 and LAMP1/2 mediated parkin-dependent mitochondrial clearance and modulated mitophagy through lysosomal dynamics. In a patient-derived xenograft (PDX) model of colon cancer, treatment with mefloquine resulted in suppression of mitophagic PINK1/PARKIN and increased mitochondrial disorder and mitochondria-induced apoptosis without apparent side effects. These results suggest that the combination of mefloquine with chemotherapeutic agents in the PDX model potentially disrupts the hierarchy of colorectal cancer cells and identify endolysosomal RAB5/7 and LAMP1/2 as promising therapeutic targets in CSCs. SIGNIFICANCE: These findings show that endosomal/lysosomal RAB5 and RAB7, which regulate mitophagy, are essential for the survival of colon cancer stem cells.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1426/F1.large.jpg.

Involvement of MAF1 homolog, negative regulator of RNA polymerase III in colorectal cancer progression.

Polymerase (Pol) III­dependent transcription controls the abundance of transfer RNAs, 5S ribosomal RNA and small non­coding RNAs within cells, and is known to serve an essential role in the maintenance of intracellular homeostasis. However, its contribution to cancer progression has not been extensively explored. The present study demonstrated that the evolutionarily conserved MAF1 homolog, negative regulator of RNA Pol III (MAF1) may be closely associated with malignant potential and poor prognosis in colorectal cancer (CRC). Notably, immunohistochemical analysis of 146 CRC surgical specimens revealed that high expression levels of MAF1 were associated with advanced tumor depth, lymph node metastasis, distant metastasis and poor prognosis. In vitro loss­of­function assays revealed that MAF1 knockdown suppressed chemoresistance and migration of CRC cancer cells. Furthermore, detailed analysis of an independent CRC dataset (n=615) demonstrated that the prognostic impact of MAF1 gene expression was particularly marked in microsatellite instability (MSI)­positive patients, who benefit from immune checkpoint blockade. High expression levels of MAF1 were revealed to be an independent prognostic indicator in MSI­positive CRC. These findings suggested that MAF1 may have an essential role in CRC progression, particularly in MSI­positive cases.

Cell-free culture conditioned medium elicits pancreatic ß cell lineage-specific epigenetic reprogramming in mice.

There are several obstacles to overcome prior to achieving cellular reprogramming of pancreatic ß cells in vitro and in vivo. The present study demonstrated that the transfer of epigenetic phenotypes was achieved in the cell-free conditioned medium (CM) of pancreatic insulinoma MIN6 cell cultures. The comparison of a subpopulation of MIN6, m14 and m9 cells indicated that MIN6-m14 cells were more prone to cellular reprogramming. Epigenetic profiling revealed that the transcription factor pancreas/duodenum homeobox protein 1 (Pdx1) was differentially associated among the clones. The culture of differentiated adipocytes in the CM of MIN6-m14 cells resulted in the induction of insulin mRNA expression, and was accompanied by epigenetic events of Pdx1 binding. The epigenetic profiling indicated that Pdx1 is preferentially associated with a previously uncharacterized region of the endoplasmic reticulum (ER) disulfide oxidase, ER oxidoreductin 1 gene. Therefore, the results of the present study indicated that the CM of MIN6 cells was able to induce a pancreatic ß cell-like phenotype in differentiated adipocytes. These data provide additional support for the utility of cell-free CM for cellular reprogramming.

Carbon ion beam radioresistant rodent cells are sensitized to trifluorothymidine exposure.

Although charged particle therapy, including carbon ion beam radiation, is a cutting-edge technology in human cancer treatment, the molecular mechanisms underlying cellular resistance to this type of therapy remain unknown. Furthermore, the chemotherapeutic agents that are most effective at overcoming cellular resistance remain unknown. In the present study, carbon ion beam radioresistant rodent cells were developed and their sensitization to trifluorothymidine (FTD), a derivative of deoxythymidine, was studied. The results of the present study demonstrated that carbon ion beam radioresistant cells were more sensitive to FTD compared with X-ray radioresistant cells. The results of the present study suggested that FTD is involved in carbon ion beam radioresistance, encouraging further study of cellular resistance to charged particle therapy for refractory human cancer.

The mitochondrial one-carbon metabolic pathway is associated with patient survival in pancreatic cancer.

The expression levels of one-carbon metabolic enzymes were investigated and observed to be correlated with clinicopathological parameters in patients with pancreatic cancer. Mitochondrial one-carbon metabolism comprises a network of biological reactions that integrate nutrient status with nucleotide synthesis, amino acid metabolism, antioxidant reduced nicotinamide adenine dinucleotide phosphate production and epigenetic methylation processes. Previous studies have reported that the hyper-activation of mitochondrial one-carbon metabolism serves a significant role in malignant cancer phenotypes. A total of 103 patients underwent surgical resection of pancreatic ductal adenocarcinomas (PDAC) at Osaka University Hospital between April 2007 and December 2013 and were enrolled in this study. Subsequently, the expression of the one-carbon metabolic enzymes methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), aldehyde dehydrogenase 1 family member L2 (ALDH1L2), and serine hydroxymethyltransferase (SHMT2) was examined using immunohistochemical analysis. The immunohistochemical analyses demonstrated that patients with high expression levels of MTHFD2, ALDH1L2 or SHMT2 had significantly poor overall survival (OS) and disease-free survival (DFS) rates, as compared with patients with low expression levels. Furthermore, multivariate Cox proportional hazards analysis indicated that MTHFD2 and ALDH1L2 were independent prognostic factors for OS and DFS, whereas SHMT2 was not predictive of DFS. However, high and low expression levels of all three folate metabolic enzymes were significantly associated with improved OS and DFS, compared with the high expression of one or two folate metabolic enzymes. The expression levels of mitochondrial one-carbon metabolic enzymes are independent prognostic factors and potential therapeutic targets for future pancreatic cancer treatments.

c-Met affects gemcitabine resistance during carcinogenesis in a mouse model of pancreatic cancer.

Pancreatic adenocarcinoma is thought to develop from histologically identifiable intraductal lesions known as pancreatic intraepithelial neoplasias (PanINs), which exhibit similar morphological and genetic features to pancreatic ductal adenocarcinoma (PDAC). Therefore, a better understanding of the biological features underlying the progression of PanIN is essential to development more effective therapeutic interventions for PDAC. In recent years, numerous studies have reported that MET proto-oncogene receptor tyrosine kinase (c-MET) is a potential marker of pancreatic cancer stem cells (CSCs). CSCs have been revealed to initiate and propagate tumors in vitro and in vivo, and are associated with a chemoresistant phenotype. However, in vivo models using a xenograft approach are limited. In the present study, the morphological phenotype, molecular alteration and biological behavior of neoplasia in Pdx-1Cre/+, KrasLSL-G12D/+ and Metflox/flox and wild-type mice was analyzed. The results demonstrated that while oncogenic KrasLSL-G12D/+ increased PanIN initiation and significantly decreased survival rate compared with wild-type mice, no additive effect of c-Met receptor signaling on PanIN progression or prognosis was observed. Following gemcitabine administration, c-Met inhibition in Kras LSL-G12D/+ mice significantly decreased the total surface area of PanIN lesions and the number of anti-proliferation marker protein Ki-67 positive cells occupying PanIN lesions compared with Met+/+ mice. In conclusion, complete inhibition of the c-Met signaling pathway with chemotherapy may be useful for the treatment of pancreatic cancer.

Fetal hepatocyte-derived culture medium elicits adipocyte differentiation to bile duct cell lineages in a mouse model.

Fetal cells in the developmental stages function with a distinct mechanism in comparison to adult tissues, which may be a useful source for regenerative medicine in postnatal medicine; however, the precise molecular mechanism remains to be elucidated fully. The present study investigated murine fetal hepatocytes, which were cultured in vitro, and the supernatants were used for the culture with murine adipose tissue-derived cells. Notably, the results indicated that fetal hepatocyte-derived culture medium elicits the induction of differentiation of adipose tissue-derived cells to bile duct cell lineages, but not to hepatocyte lineages in mice. This indicates that fetal cells possess the multi potentials, which are already absent in adults, and may be useful for regenerative medicine in future.