ABSTRACT
AIM: There are conflicting data on the biological and prognostic significance of disseminated tumour cells (DTCs) in the bone marrow of colorectal cancer patients since bone metastasis is rare in this disease. The study aimed to determine the origin of bone marrow DTCs using human colorectal cancer cells in in vivo and in vitro experimental settings. METHOD: CD1 nude female mice were xenotransplanted with SW620 cells (a colorectal cancer cell line isolated from a male patient) injected in the colon wall. At autopsy, the presence of SW620 in the bone marrow (BM), colon and other organs/tissues was recognized by detection of the epithelial marker cytokeratin-19 (CK19) and Y chromosome. In addition SW620 cells or their conditioned medium were cultured with human BM cells. RESULTS: Macroscopically evident CK19+/Y-chromosome-positive tumours developed only in five mice receiving SW620 cells while putative DTCs (CK19+) were found in the bone marrow of all treated mice. Most of these CK19+ cells were Y chromosome negative, only few being Y chromosome positive. In vitro SW620 cells or their conditioned medium induced CK19 expression in cultured human bone marrow cells. CONCLUSION: Experimental colorectal cancer can induce the appearance of two distinct CK19+ cell populations in the bone marrow, one of metastatic origin and the other of murine origin. These findings suggest that bone marrow cells may undergo phenotypic modifications induced by cancer cells.
Subject(s)
Bone Marrow Cells/pathology , Bone Marrow/pathology , Carcinoma/pathology , Colonic Neoplasms/pathology , Neoplasms, Experimental/pathology , Animals , Bone Marrow/metabolism , Bone Marrow Cells/metabolism , Bone Marrow Examination , Carcinoma/metabolism , Cell Line, Tumor , Colonic Neoplasms/metabolism , Female , Humans , Keratin-19/metabolism , Male , Mice , Mice, Nude , Neoplasms, Experimental/metabolism , Y ChromosomeABSTRACT
BACKGROUND: Androgen receptors (ARs) act as transcription factors. An increased AR activity could be due either to mutations or to an increased expression of the receptor. AR mutations involving the hormone binding domain could increase AR function and promote carcinogenesis, as suggested for prostate cancer. AIMS: Herein, we evaluated qualitative (point mutations involving the hormone binding domain) and quantitative AR alterations and their possible correlation with cell proliferation and tumour grading. MATERIALS: Carcinomatous and non-cancerous surrounding liver tissue was collected from 14 Caucasian patients with hepatocarcinoma. They were all affected by cirrhosis with different aetiologies. METHODS: AR missense mutations, AR mRNA and protein levels, AR distribution in the liver, liver cell proliferation, and tumour staging were evaluated by DNA sequencing, quantitative real-time PCR, Western blot analysis, immunofluorescence, PCNA immunostaining, and conventional histological techniques, respectively. RESULTS: AR gene regions encoding the hormone binding domain did not contain any missense mutation. AR mRNA and protein levels were increased in hepatocarcinoma compared to non-cancerous surrounding tissue. Cell proliferation was significantly increased in the tumour compared to non-cancerous surrounding tissue. CONCLUSIONS: Mutations of the AR regions studied were not involved in hepatocarcinogenesis. Elevated AR levels in transformed cells could have a tumour promoting effect by stimulating cell growth.
Subject(s)
Androgen-Binding Protein/genetics , Liver Neoplasms/genetics , Mutation, Missense/genetics , Receptors, Androgen/genetics , Adult , Aged , Aged, 80 and over , Androgen-Binding Protein/metabolism , Blotting, Western , Cell Proliferation , Humans , Immunohistochemistry , Liver/metabolism , Liver Neoplasms/metabolism , Male , Middle Aged , Point Mutation/genetics , Protein Structure, Tertiary , Receptors, Androgen/metabolismABSTRACT
BACKGROUND AND AIMS: Epidemiological data demonstrate that HCC is prevalent in men compared to women. Herein, we examined the effect of gonadectomy in a murine model that spontaneously develops HCC. ANIMALS AND METHODS: Thirty-two male and 26 female HBV transgenic mice [Tg (Alb-1 HBV) Bri 44] underwent surgical castration or sham operation. At the 18th month, serum samples were collected and all mice were sacrificed. Liver weight and volume were evaluated, each liver was cut into 1.5-mm-thick consecutive slices and nodules were examined on freshly isolated tissue. Consecutive histological sections obtained from each liver slice were evaluated to confirm the diagnosis of HCC. RESULTS: Sham-operated females showed a significantly lower neoplastic growth compared to sham-operated males. This difference disappeared when females underwent gonadectomy. In males, neoplastic growth was not influenced by gonadectomy. Testosterone and estradiol levels were profoundly modified by gonadectomy in both males and females. The testosterone/estradiol ratio in gonadectomized females increased 4.5-fold compared to that in sham-operated females, becoming more similar to the ratio observed in castrated and sham-operated male mice. CONCLUSIONS: HCC growth in our experimental model was not simply influenced by the levels of testosterone or estradiol, taken singularly, but depended on their ratio.
