MSH2 gene dosage mediates azathioprine-induced carcinogenesis in mice

in Journal of the National Cancer Institute (2010)

Prognostic Value of Bone Sialoprotein Expression in Clinically Localized Human Prostate Cancer

in Journal of the National Cancer Institute (1998), 90(13), 1000-8

BACKGROUND: Bone sialoprotein (BSP), a bone matrix protein, was recently found to be expressed ectopically in breast cancer and to have a statistically significant association with poor prognosis and the ... [more ▼]

BACKGROUND: Bone sialoprotein (BSP), a bone matrix protein, was recently found to be expressed ectopically in breast cancer and to have a statistically significant association with poor prognosis and the development of bone metastases in that disease. These data prompted us to investigate whether BSP might also be expressed in human prostate cancer, which often metastasizes to bone, and be predictive for progression risk. METHODS: Tissue sections from 180 patients who had undergone a radical prostatectomy for localized prostate cancer were analyzed immunohistochemically for BSP expression. Biochemical progression was defined as an increasing serum prostate-specific antigen level of 0.5 ng/mL or more. Statistical analysis was used to assess associations between pathologic findings and level of BSP expression, and a Cox proportional hazards model was used to determine which clinical and histologic parameters, including stage, Gleason score, and BSP expression (immunostaining intensity and extent), were independently associated with biochemical progression. All P values were two-sided. RESULTS: Most of the prostate cancer lesions examined (78.9%) expressed detectable levels of BSP, compared with no or low expression in the adjacent normal glandular tissue. A statistically significant association was found between BSP expression and biochemical progression in both univariate and multivariate analyses. After a follow-up interval of 3 years, the biochemical relapse rate was 36.7% (95% confidence interval [CI] = 23.4%-47.7%) in patients whose tumors expressed high levels of BSP compared with 12.1% (95% CI = 2.3%-20.8%) in patients whose tumors expressed no or a low detectable level of the protein (logrank test, P = .0014). BSP expression status could identify those patients at higher risk of biochemical progression (logrank test, P<.05) among patients with moderately differentiated tumors or with pathologically confined tumors. CONCLUSIONS: To our knowledge, this study is the first to demonstrate BSP expression in human prostate cancer and to highlight the protein's statistically significant prognostic value in patients with clinically confined prostate adenocarcinomas. [less ▲]

Prevention of Murine Radiogenic Thymic Lymphomas by Tumor Necrosis Factor or by Marrow Grafting

in Journal of the National Cancer Institute (1996), 88(12), 824-31

BACKGROUND: Split-dose irradiation (1.75 Gy given weekly for 4 weeks) of C57BL/Ka mice induces the emergence of preleukemic cells (PLCs). These cells develop into leukemic cells after a latency period of ... [more ▼]

BACKGROUND: Split-dose irradiation (1.75 Gy given weekly for 4 weeks) of C57BL/Ka mice induces the emergence of preleukemic cells (PLCs). These cells develop into leukemic cells after a latency period of 3-6 months. The survival and transformation of PLCs are dependent on radiation-induced alterations of the thymic epithelium and of resident lymphocyte (i.e., thymocyte) subpopulations in the thymus. PLCs can be eliminated, concomitantly with the restoration of the thymus, by grafting bone marrow cells immediately after the last irradiation. Our hypothesis was that any agent able to restore the thymus after leukemogenic irradiation would exert the same effects as a bone marrow graft. Tumor necrosis factor-alpha (TNF-alpha) is one such possible agent, since it has been shown to modulate some functions of the thymic epithelium and thymocyte subpopulations. PURPOSE: The goal of this study was to assess the ability of repeated intraperitoneal injections of TNF-alpha to functionally replace bone marrow transplantation in the restoration of normal intrathymic lymphopoiesis and in the prevention of thymic lymphomas in split-dose-irradiated mice. METHODS: We replaced the bone marrow graft with repeated injections of TNF-alpha (25 000 U/injection) in the split-dose-irradiated (4 x 1.75 Gy) C57BL/Ka mouse model. We analyzed the expression of the cell differentiation markers CD4 and CD8 on thymocytes by flow cytometry. We also studied the thymic environment by isolating thymic nurse cells, the bone marrow prothymocyte activity by analyzing thymic repopulation, and the evolution of PLCs by an in vivo transplantation assay. Local production of TNF-alpha after bone marrow grafting was examined by in situ hybridization. Injections of anti-TNF-alpha antibodies were given to split-dose-irradiated mice to test the effect of neutralizing TNF-alpha in vivo. One-way analysis of variance and Newman-Keuls two-tailed tests were used to test statistical significance. RESULTS: Multiple injections of TNF-alpha into split-dose-irradiated mice did not influence bone marrow prothymocyte activity but restored thymocyte subpopulations and thymic epithelium, induced the disappearance of PLCs, and prevented the development of lymphomas. Moreover, a bone marrow graft significantly stimulated intrathymic production of TNF-alpha messenger RNA (P<.01), and anti-TNF-alpha antibodies partially inhibited the antilymphomatous effects of bone marrow graft in split-dose-irradiated mice (P<.05). CONCLUSION: These data strongly suggest that TNF-alpha is a mediator that is involved in the mechanisms by which bone marrow transplantation functions to prevent thymic lymphomas in split-dose-irradiated mice. IMPLICATIONS: Cytokines might be used in some biological systems, particularly in the hemopoietic system, as a therapeutic agent for the secondary prevention of cancer. [less ▲]

Enhancement of metastatic potential of murine and human melanoma cells by laminin receptor peptide G: attachment of cancer cells to subendothelial matrix as a pathway for hematogenous metastasis.

in Journal of the National Cancer Institute (1993), 85(3), 235-40

BACKGROUND: Stable anchorage of circulating cancer cells to the vasculature is a critical step in the formation of hematogenous metastases. Although the basement membrane glycoprotein laminin clearly ... [more ▼]

BACKGROUND: Stable anchorage of circulating cancer cells to the vasculature is a critical step in the formation of hematogenous metastases. Although the basement membrane glycoprotein laminin clearly plays a crucial role in this event, the exact interactive pathways among cancer cells, laminin, and the vessel wall have not been elucidated. In a previous study, we identified synthetic peptide G, which contains the laminin-binding domain of the 67-kd laminin receptor and which inhibits tumor cell adhesion to endothelial cells. PURPOSE: To assess the role of the interaction between laminin and the 67-kd laminin receptor in hematogenous metastasis formation, we studied the effect of peptide G on melanoma cell behavior in vivo and in vitro. METHODS: The effect of peptide G and control peptides was studied in vivo on lung retention and colonizing potential of murine (B16BL6) and human (A2058) melanoma cells injected intravenously in C57BL/6 and nude mice, respectively. In addition, their effect on cell adhesion and chemotaxis to laminin and on binding of iodine 125-labeled laminin to cells was studied in vitro. RESULTS: In vivo, pretreatment of cells with peptide G resulted in a two- to 10-fold significant increase in the number of experimental lung metastases. A significant relative increase in lung retention of peptide G-treated tumor cells was observed 48 hours after injection, although after 4 hours a partial reduction was observed. In vitro, peptide G significantly increased laminin binding and cancer cell adhesion to laminin and subendothelial matrix, whereas chemotaxis to laminin was significantly inhibited. CONCLUSIONS: Peptide G differentially affected the biological response of cancer cells to laminin. In vitro, it increased laminin binding and cell adhesion to laminin and subendothelial matrix, whereas it inhibited cell chemotaxis to laminin. In vivo, the overall effect of peptide G was an augmentation of lung metastasis. IMPLICATIONS: Our findings suggest that direct adhesion of tumor cells to the subendothelial matrix is a main pathway for hematogenous metastases and that tumor cell-matrix interaction may be more relevant than tumor cell-endothelial cell attachment in this process. [less ▲]

Increased expression of the laminin receptor in human colon cancer.

in Journal of the National Cancer Institute (1991), 83(1), 29-36

It has been proposed that among the various cell-surface proteins capable of interacting with laminin, the 67-kd high-affinity laminin receptor plays a crucial role during tumor invasion and metastasis ... [more ▼]

It has been proposed that among the various cell-surface proteins capable of interacting with laminin, the 67-kd high-affinity laminin receptor plays a crucial role during tumor invasion and metastasis. In this study, the expression of laminin-receptor-precursor messenger RNA (mRNA) and 67-kd protein was analyzed in human colon adenocarcinoma. In 22 of 23 patients with colon cancer, we found a 2- to 23-fold increase in levels of laminin-receptor-precursor mRNA in the cancer tissues compared with those in matched normal adjacent colonic mucosa. In 10 of 11 cases studied, the level of 67-kd laminin receptor, detected by affinity-purified anti-laminin-receptor synthetic peptide antibodies on immunoblots of matched tumor and normal tissue extracts, was higher in the colon carcinoma tissue. Immunodetection of laminin receptor in tissue sections using anti-laminin-receptor-peptide antibodies confirmed that the increased expression of laminin receptor was specifically associated with the cancer cells. In a series of 72 paraffin sections of colon lesions, we observed a correlation between the expression of the laminin receptor and the Dukes' classification. Our observations indicate that increased expression of laminin-receptor-precursor mRNA is associated with enhanced levels of the 67-kd laminin receptor as well as with the invasive phenotype of colon carcinoma. Detection of this metastasis-associated gene product may be a valuable adjunct in the evaluation of human colon cancer. [less ▲]

Modulation of laminin receptor expression by estrogen and progestins in human breast cancer cell lines.

in Journal of the National Cancer Institute (1989), 81(10), 781-8

The effects of estradiol and two synthetic progestins (ORG2058 and R5020) on the expression of the high-affinity, metastasis-associated laminin receptor in two human breast carcinoma cell lines were ... [more ▼]

The effects of estradiol and two synthetic progestins (ORG2058 and R5020) on the expression of the high-affinity, metastasis-associated laminin receptor in two human breast carcinoma cell lines were examined. The T47D cell line contains estrogen and progesterone receptors, but the MDA-MB 231 cell line lacks both receptors. Treatment of T47D cells with 10(-9) M estradiol alone results in a three-fold increase (P less than or equal to .05) in the steady-state level of laminin receptor mRNA determined by RNA blot analysis as well as in cell-surface, laminin receptor expression that is evaluated by immunofluorescence. No effects of estradiol on the receptor-negative MDA-MB 231 cells were observed. Untreated and steroid-treated MDA-MB 231 cells had higher levels of laminin receptor mRNA than did untreated or estradiol-treated T47D cells. A more dramatic increase (five-fold; P less than or equal to .005) of mRNA and cell-surface expression in T47D cells was observed after treatment with estradiol plus 10(-8) M progestin or with progestin alone. Estradiol treatment also increased chemotaxis and haptotaxis of T47D cells but not of MDA-MB 231 cells to laminin; it had no effect on the attachment of these latter cells to laminin. Interestingly, treatment with estradiol plus progestin or progestin alone significantly increased the attachment of T47D cells to laminin but did not have an effect on either haptotaxis or chemotaxis to laminin. These results suggest that the various cell-laminin interactions are mediated by different mechanisms. The augmentation of laminin receptor mRNA by estrogen and progesterone treatment in hormone receptor-positive cells, but not in cells that lack these receptors, may relate functionally to the difference in the clinical aggressiveness between classes of breast cancers. [less ▲]

Effects of marrow grafting on preleukemia cells and thymic nurse cells in C57BL/Ka mice after a leukemogenic split-dose irradiation.

in Journal of the National Cancer Institute (1986), 77(5), 1079-85

A split-dose regimen of whole-body irradiation (4 X 175 rad at weekly intervals) induced thymic lymphomas in C57BL/Ka mice after a latent period of 3-9 months. Meanwhile, preleukemia cells arose in the ... [more ▼]

A split-dose regimen of whole-body irradiation (4 X 175 rad at weekly intervals) induced thymic lymphomas in C57BL/Ka mice after a latent period of 3-9 months. Meanwhile, preleukemia cells arose in the thymus and bone marrow and persisted until the onset of lymphomas. Simultaneously, thymic lymphopoiesis was impaired; thymocyte numbers were subnormal and thymic nurse cells disappeared in a progressive but irreversible fashion. The depletion of these lymphoepithelial complexes, which are normally involved in the early steps of thymic lymphopoiesis, was related to altered prothymocyte activity in bone marrow and to damaged thymic microenvironment, perhaps as a consequence of the presence of preleukemia cells. The grafting of normal bone marrow cells after irradiation prevented the development of lymphomas. However, marrow reconstitution did not inhibit the induction of preleukemia cells. They disappeared from the thymus during the second part of the latent period. At the same time, thymic lymphopoiesis was restored; thymocytes and nurse cell numbers returned to normal as a consequence of the proliferation of grafted marrow-derived cells within the thymus. The results thus demonstrated an intimate relationship between preleukemia cells and an alteration of thymic lymphopoiesis, which particularly involved the nurse cell microenvironment. Some preleukemia cells in marrow-reconstituted, irradiated mice derived from the unirradiated marrow inoculate. Thus these cells acquired neoplastic potential through a factor present in the irradiated tissues. The nature of this indirect mechanism was briefly discussed. [less ▲]