ABSTRACT
Liver metastasis is the major cause of death for patients with colorectal cancer. Despite treatment with surgery and chemotherapy, patient outcomes are quite unfavourable. Thus, there is an urgent need to develop new treatment strategies with the associated establishment of good animal models. Metastatic disease can be modelled using patient-derived orthotopic xenografts, which accurately replicate intra-tumoral heterogeneity so that various chemotherapeutic agents can be tested on individual tumours to aid in clinical decision-making. The objective of this study was to develop metastatic colorectal tumours in athymic nude mice by implanting fresh tumour fragments into mouse liver parenchyma. Metastatic tumours were successfully propagated in mice following transplantation from human patients, then serially implanted in second and third-generation mice. Morphologic and immunohistochemical characteristics indicate that xenografts recreate the tumour architecture and mismatch repair gene expression for MLH1, MSH2, MSH1, and PMS2. After tumour implantation during the first passage, the time of tumour growth decreased without loss of tumour identity. Post-transplantation lymphoproliferative disease was observed in one case. This pilot study was successful in establishing the institutional PDX preclinical platform to study new therapeutic strategies, disease progression biomarkers, and treatment responsiveness.
Subject(s)
Colorectal Neoplasms/pathology , Disease Models, Animal , Liver Neoplasms/pathology , Animals , Biomarkers, Tumor/metabolism , DNA Mismatch Repair/genetics , Disease Progression , Female , Gene Expression Regulation, Neoplastic , Humans , Liver Neoplasms/genetics , Liver Neoplasms/secondary , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Pilot Projects , Xenograft Model Antitumor AssaysABSTRACT
AIMS: GATA3 has been reported as a specific urothelial marker among organs in the pelvic region, and has been classified as highly sensitive and specific for urothelial and breast carcinomas. Our aim was to verify GATA3 expression in extramammary Paget disease, and to determine whether it can be use to differentiate primary vulvar Paget disease from pagetoid urothelial intraepithelial neoplasia (PUIN). We also analysed HER2 protein expression and HER2 gene amplification and their roles as prognostic factors in extramammary Paget disease. METHODS AND RESULTS: We analysed GATA3 and HER2 expression in 11 primary vulvar Paget disease cases and two PUIN cases. All cases showed nuclear expression of GATA3. Of 13 cases, five were equivocal for HER2 expression (score 2+) and one was positive (3+). Fluorescence in-situ hybridization results showed amplification in two of these six cases. Both HER2-amplified cases were invasive. CONCLUSION: GATA3 was positive in all extramammary Paget disease cases tested (13 cases), and it has no value for differentiating between primary and secondary vulvar Paget disease from the urological tract. HER2 amplification might confer an aggressive and invasive pattern in primary vulvar Paget disease, as both amplified cases showed an invasive pattern.
Subject(s)
Biomarkers, Tumor/analysis , Carcinoma in Situ/diagnosis , GATA3 Transcription Factor/biosynthesis , Paget Disease, Extramammary/diagnosis , Urologic Neoplasms/diagnosis , Vulvar Neoplasms/diagnosis , Adult , Aged , Aged, 80 and over , Carcinoma in Situ/metabolism , Carcinoma in Situ/pathology , Diagnostic Errors , Female , GATA3 Transcription Factor/analysis , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Middle Aged , Paget Disease, Extramammary/metabolism , Paget Disease, Extramammary/pathology , Receptor, ErbB-2/analysis , Urologic Neoplasms/metabolism , Urologic Neoplasms/pathology , Vulvar Neoplasms/metabolism , Vulvar Neoplasms/pathologyABSTRACT
BACKGROUND: The development of targeted therapies has undoubtedly broadened therapeutic options for patients with colorectal cancer (CRC). The use of bevacizumab to reduce angiogenesis has been associated with improved clinical outcomes. However, an urgent need for prognostic/predictive biomarkers for anti-angiogenic therapies still exists. METHODS: Clinical data of 105 CRC patients treated with bevacizumab in conjunction with chemotherapy were analyzed. The expression of vascular endothelial growth factor (VEGF) receptors, NOTCH1 receptor and its ligand DLL4 were determined by immunohistochemistry. Tumor samples were arranged on a tissue microarray. The association between protein expression and clinicopathological characteristics and outcomes was determined. RESULTS: Bevacizumab was administered as a first-line of treatment in 70.5 % of our cases. The median progression-free survival (PFS) was 10.2 months. The median overall survival (OS) of the total cohort was 24.4 months. Bevacizumab, as the first-line of treatment, and the presence of liver metastasis were independently associated with objective response rate. Membrane VEGFR1 and VEGFR3 expressions were associated with the presence of lung metastasis; interestingly, VEGFR3 was associated with less liver metastasis. NOTCH1 expression was associated with lymph node metastasis. There was a trend toward association between improved PFS and lower NOTCH1 expression (p = 0.06). Improved OS was significantly associated with lower NOTCH1 expression (p = 0.01). In a multivariate analysis, ECOG (Eastern Cooperative Oncology Group) performance status, liver metastasis, histological grade, and NOTCH1 expression were independently associated with OS. CONCLUSION: Our findings illustrated the expression profile of angiogenesis-related proteins and their association with clinicopathological characteristics and outcomes. NOTCH1 expression is a detrimental prognostic factor in metastatic CRC patients treated with chemotherapy plus bevacizumab.
