Effective development of targeted anticancer agents includes the definition of the optimal biological dose and biomarkers of drug activity. Currently available preclinical models are not optimal to this end. We aimed at generating a model for translational drug development using pancreatic cancer as a prototype. Resected pancreatic cancers from 14 patients were xenografted and expanded in successive groups of nude mice to develop cohorts of tumor-bearing mice suitable for drug therapy in simulated early clinical trials.The xenografted tumors maintain their fundamental genotypic features despite serial passages and recapitulate the genetic heterogeneity of pancreatic cancer. The in vivo platform is useful for integrating drug screening with biomarker discovery. Passages of tumors in successive cohorts of mice do not change their susceptibility to anticancer agents and represent a perpetual live bank, facilitating the application of new technologies that will result in the creation of an integrated stable database of tumor-drug response data and biomarkers.

Serum miR-21 is a promising biomarker for the early detection and prognosis of CRC.

Hyperglycemia might be associated with impaired microvascular function after AMI, resulting in a larger infarct size and worse functional recovery.

Objective To evaluate the ability of Epithelial-to-mesenchymal transition (EMT)-related microRNAs (miRNAs) as serum biomarkers for prognosis and prediction of metastasis in colorectal cancer (CRC) patients. Background EMT-related miRNAs drive CRC progression and metastasis. However, their potential as serum biomarkers in CRC has not been studied. Methods This was a three-phase study using 446 colorectal specimens. In the first phase, we selected candidate miRNAs associated with metastasis by analyzing the expression of four miR-200 family members (miR-200b, -200c, -141 and -429) in serum samples from 12 stage I and IV CRC patients. The second phase involved independent validation of candidate miRNAs in serum from 182 CRC patients and 24 controls. Lastly, we analyzed expression in matched 156 tumor tissues from 182 CRC patients, as well as an independent set of 20 matched primary CRC and corresponding liver metastases to identify source of circulating miRNAs. RESULTS Following initial screening, miR-200c was selected as the candidate serum miRNA best associated with metastasis. Validation analysis revealed that serum miR-200c levels were significantly higher in stage IV compared with stage I–III CRCs. High serum miR-200c demonstrated a significant positive correlation with lymph node, distant metastasis and prognosis (P=0.0026, P=0.0023 and P=0.0064, respectively). More importantly, serum miR-200c was an independent predictor for lymph node metastasis (OR=4.81, 95% CI=1.98–11.7 P=0.0005), tumor recurrence (HR=4.51, 95% CI=1.56–13.01 P=0.005) and emerged as an independent prognostic marker for CRC (HR: 2.67, 95%CI: 1.28–5.67, P=0.01). CONCLUSION Serum miR-200c has a strong potential to serve as a noninvasive biomarker for CRC prognosis and predicting metastasis.

Expression of CD133, OCT4, and SOX2 may predict distant recurrence and poor prognosis of rectal cancer patients treated with preoperative CRT. Correlations among these genes may be associated with tumor regrowth and metastatic relapse after CRT.

Preoperative PNI is a useful predictor of postoperative complications and survival in patients with colorectal cancer.

Background: Systemic inflammation via host-tumor interactions is currently recognized as a hallmark of cancer. The aim of this study was to evaluate the prognostic value of various combinations of inflammatory factors using preoperative blood, and to assess the clinical significance of our newly developed inflammatory score in colorectal cancer (CRC) patients. Method: In total 477 CRC patients from the discovery and validation cohorts were enrolled in this study. We assessed the predictive impact for recurrence using a combination of nine inflammatory markers in the discovery set, and focused on lymphocyte-C-reactive protein ratio (LCR) to elucidate its prognostic and predictive value for peri-operative risk in both cohorts. Results: A combination of lymphocytic count along with C-reactive protein levels demonstrated the highest correlation with recurrence compared with other parameters in CRC patients. Lower levels of preoperative LCR significantly correlated with undifferentiated histology, advanced T stage, presence of lymph node metastasis, distant metastasis, and advanced stage classification. Decreased preoperative LCR (using an optimal cut-off threshold of 6000) was an independent prognostic factor for both disease-free survival and overall survival, and emerged as an independent risk factor for postoperative complications and surgical-site infections in CRC patients. Finally, we assessed the clinical feasibility of LCR in an independent validation cohort, and confirmed that decreased preoperative LCR was an independent prognostic factor for both disease-free survival and overall survival, and was an independent predictor for postoperative complications and surgical-site infections in CRC patients. Conclusion: Preoperative LCR is a useful marker for perioperative and postoperative management of CRC patients.

Notch1 transactivates Notch3 to drive terminal differentiation in stratified squamous epithelia. Notch1 and other Notch receptor paralogs cooperate to act as a tumor suppressor in squamous cell carcinomas (SCCs). However, Notch1 can be stochastically activated to promote carcinogenesis in murine models of SCC. Activated form of Notch1 promotes xenograft tumor growth when expressed ectopically. Here, we demonstrate that Notch1 activation and epithelial–mesenchymal transition (EMT) are coupled to promote SCC tumor initiation in concert with transforming growth factor (TGF)-β present in the tumor microenvironment. We find that TGFβ activates the transcription factor ZEB1 to repress Notch3, thereby limiting terminal differentiation. Concurrently, TGFβ drives Notch1-mediated EMT to generate tumor initiating cells characterized by high CD44 expression. Moreover, Notch1 is activated in a small subset of SCC cells at the invasive tumor front and predicts for poor prognosis of esophageal SCC, shedding light upon the tumor promoting oncogenic aspect of Notch1 in SCC.