ABSTRACT
Intratumoral heterogeneity within individual breast tumors is a well-known phenomenon that may contribute to drug resistance. This heterogeneity is dependent on several factors, such as types of oncogenic drivers and tumor precursor cells. The purpose of our study was to engineer a mouse mammary tumor model with intratumoral heterogeneity by using defined genetic perturbations. To achieve this, we used mice with knockout (-/-) of Ink4a/Arf, a tumor suppressor locus; these mice are known to be susceptible to non-mammary tumors such as fibrosarcoma. To induce mammary tumors, we retrovirally introduced an oncogene, HRAS(G12V), into Ink4a/Arf(-/-) mammary cells in vitro, and those cells were inoculated into syngeneic mice mammary fat pads. We observed 100% tumorigenesis. The tumors formed were negative for estrogen receptor, progesterone receptor and HER2. Further, they had pathological features similar to those of human triple-negative breast cancer (TNBC) (for example, pushing borders, central necrosis). The tumors were found to be heterogeneous and included two subpopulations: CD49f(-) quiescent cells and CD49f(+)cells. Contrary to our expectation, CD49f(-) quiescent cells had high tumor-initiating potential and CD49f(+)cells had relatively low tumor-initiating potential. Gene expression analysis revealed that CD49f(-) quiescent cells overexpressed epithelial-to-mesenchymal transition-driving genes, reminiscent of tumor-initiating cells and claudin-low breast cancer. Our animal model with intratumoral heterogeneity, derived from defined genetic perturbations, allows us to test novel molecular targeted drugs in a setting that mimics the intratumoral heterogeneity of human TNBC.
Subject(s)
Cell Transformation, Neoplastic/genetics , Integrin alpha6/metabolism , Mammary Neoplasms, Experimental/metabolism , Neoplastic Stem Cells/metabolism , Triple Negative Breast Neoplasms/metabolism , Animals , Cell Transformation, Neoplastic/metabolism , Cyclin-Dependent Kinase Inhibitor p16/genetics , Female , Flow Cytometry , Immunohistochemistry , Mammary Neoplasms, Experimental/genetics , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Neoplastic Stem Cells/pathology , Oligonucleotide Array Sequence Analysis , Proto-Oncogene Proteins p21(ras)/genetics , Real-Time Polymerase Chain Reaction , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathologyABSTRACT
We described a case of advanced gastric cancer with multiple liver metastases, who was placed on neoadjuvant chemotherapy using CDDP and 5-FU (FP therapy) with a marked reduction in tumor load. The case was a 67-year-old male, who was admitted with a Borrmann III type advanced gastric cancer with multiple liver metastases. FP chemotherapy was carried out two times as neoadjuvant chemotherapy. As a result, both primary cancer and the metastatic tumors showed a remarkable reduction. Then, total gastrectomy with combined resections of spleen and transverse colon was done, and a reservoir was inserted into the hepatic artery. Postoperatively, intrahepatic arterial infusion of CDDP with oral administration of 5-FU was done in the outpatient clinic for about eleven months. But thirteen months later, he died from the rapid recurrence of the tumor.
Subject(s)
Adenocarcinoma/secondary , Adenocarcinoma/therapy , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Liver Neoplasms/secondary , Liver Neoplasms/therapy , Stomach Neoplasms/therapy , Aged , Chemotherapy, Adjuvant , Cisplatin/administration & dosage , Drug Administration Schedule , Fluorouracil/administration & dosage , Gastrectomy , Humans , MaleABSTRACT
A guinea pig-lethal line of Leptospira interrogans serovar copenhageni strain Shibaura, but not an avirulent line of the same strain, moved in larger numbers toward hemoglobin than toward distilled water (control) in a U-shaped polypropylene tube. L. interrogans serovar lai strains 017 and KH-1, which were also guinea pig lethal, showed a similar move to hemoglobin. No such move toward hemoglobin was shown by 14 avirulent strains of L. interrogans (with one exception) or any of the 8 strains of L. biflexa tested.
Subject(s)
Hemoglobins , Leptospira/pathogenicity , Animals , Cattle , Chemotaxis , In Vitro TechniquesABSTRACT
A method for a serological diagnosis of syphilis is presented, in which a thin-layer ion-selective electrode is used for monitoring the complement-mediated immune lysis of antigen-sensitized phospholipid liposomes in microlitre sample volumes. The liposomes are loaded with tetrapentylammonium ions (TPA(+)) which are then released from the liposomes by the immuno reaction and are monitored by a TPA(+) ion-selective electrode. This is a direct but much amplified measure of the syphilitic antibodies to be assayed. The principles and evaluation of the method are given. The results have been compared and correlated with those of a conventional method.
