Biomedical subjects

F W Orr

Publications and source records attributed to F W Orr.

78 records · Page 5Linked to original sources

PubMedDate not supplied

Preferential growth of metastatic tumors at the pleural surface of mouse lung.

In an experimental model of lung metastasis we have observed that more metastatic tumors are located on the pleura of the lung than in the parenchyma. To study possible reasons for this differential pattern we have now related the initial distribution of injected tumor cells to the later location and growth rate of metastases in different regions of the lung in C57bl/6 mice. It was found that labeled murine fibrosarcoma cells were evenly distributed throughout the lungs 24 h after intravenous injection into controls and animals previously treated with bleomycin or by exposure to hyperoxia. These treatments, known to induce pulmonary endothelial injury, were associated with increased tumor cell localization in the lung. In all cases, using morphometric methods, we found that after 2 weeks, approximately 75 per cent of metastatic tumors were located at the pleura. By [3H]thymidine labeling in autoradiographs, pleural tumors in all experimental groups had a growth rate 14 times the growth rate of tumors located in the internal regions of the lung. In vitro, the fibrosarcoma cells proliferated more rapidly on connective tissue matrices prepared from normal pleuras than they did on matrices from the remainder of the lung. Protease digestion of these matrices indicated differences in composition with more insoluble collagen, probably type I collagen, present at the pleura. These data suggest that, in spite of the initial random distribution and localization of tumor cells in the lung, there is preferential growth of metastatic tumors at the pleura which may be related to regional differences in the composition of the extracellular matrix.

Animals↗

PubMedDate not supplied

Interactions between cancer cells and the microvasculature: a rate-regulator for metastasis.

Hematogenous metastasis is a major consideration in the staging, treatment and prognosis of patients with cancer. Key events affecting hematogeneous metastasis occur in the microvasculature. This is a brief, selective review of some interactions involving cancer cells and the microvasculature in pathologic sequence, specifically: (1) intravasation of cancer cells; (2) the arrest of circulating cancer cells in the microvasculature; (3) cancer cell trauma associated with arrest; (4) microvascular trauma; (5) the inflammatory; and (6) the hemostatic coagulative responses associated with arrest, and finally (7) angiogenesis, leading to tumor vascularization. The evidence shows that through a series of complex interactions with cancer cells, the microvasculature acts as a rate-regulator for the metastatic process, in addition to providing routes for cancer cell dissemination and arrest sites for cancer cell emboli.

Cell Adhesion↗

PubMedDate not supplied

Adhesion molecules and their role in cancer metastasis.

This article describes various adhesion molecules and reviews evidence to support a mechanistic role for adhesion molecules in the process of cancer metastasis. A variety of evidence supports the involvement of specific adhesion molecules in metastasis. 1. For example, some cancer cells metastasize to specific organs, irrespective of the first organ encountered by the circulating cancer cells. This ability to colonize a specific organ has been correlated with the preferential adhesion of the cancer cells to endothelial cells derived from the target organ. This suggests that cancer cell/endothelial cell adhesion is involved in cancer cell metastasis and that adhesion molecules are expressed on the endothelium in an organ-specific manner. 2. Further, inclusion of peptides that inhibit cell adhesion, such as the YIGSR- or RGD-containing peptides, is capable of inhibiting experimental metastasis. 3. Metastasis can be enhanced by acute or chronic inflammation of target vessels, or by treatment of animals with inflammatory cytokines, such as interleukin-1. In vitro, cancer cell/endothelial cell adhesion can be enhanced by pretreating the endothelial cell monolayer with cytokines, such as interleukin-1 or tumor necrosis factor-alpha. This suggests that, in addition to organ-specific adhesion molecules, a population of inducible endothelial adhesion molecules is involved and is relevant to metastasis. 4. Further support for this model is found in the comparison to leukocyte/endothelial adhesion during leukocyte trafficking. Convincing evidence exists, both in vivo and in vitro, to demonstrate an absolute requirement for leukocyte/endothelial adhesion before leukocyte extravasation can occur. The relevance of this comparison to metastasis is reinforced by the observation that some of the adhesion molecules involved in leukocyte/endothelial adhesion are also implicated in cancer cell/endothelial adhesion. The involvement of adhesion molecules suggests a potential therapy for metastasis based on interrupting adhesive interactions that would augment other treatments for primary tumors.

Animals↗

PubMedDate not supplied

Biodegradation of polydioxanone in bone tissue: effect on the epiphyseal plate in immature rabbits.

Implants of polydioxanone (PDS), 1.3 mm in diameter, were operatively fixed in the juxta-epiphyseal area of the right proximal tibial metaphysis in six rabbits and were driven into a drill hole of equal bore through the right proximal tibial epiphyseal plate in ten rabbits. The PDS implants had biodegraded almost completely in cortical bone at 16 weeks without any significant sign of inflammation or foreign body reaction. The PDS implants did not cause any growth disturbance. Histologic studies, however, showed that seven of 10 rabbits demonstrated significant osseous bridge formation across the epiphyseal plate.

Animals↗

PubMedDate not supplied

Human metastatic prostate PC3 cell lines degrade bone using matrix metalloproteinases.

Bone metastases are often associated with osteolysis and subsequent pathological fractures. To determine if metastatic human cancer cells can directly degrade non-mineralized and mineralized bone, we used prostate PC3 adenocarcinoma cell lines, which were originally established from skeletal metastases. We show that PC3 cells and their conditioned medium degraded non-mineralized, osteoid-like radiolabelled extracellular matrices from human Saos2 and U2OS osteoblast-like cells. These cells also directly degraded mineralized bone by inducing (45)Ca release from rat fetal calvariae and forming resorption pits on bone slices, an effect increased by transforming growth factor-beta(1). A role for matrix metalloproteinases in degradation was shown by: (1) stimulation by the phorbol ester TPA of PC3-induced matrix degradation and release of matrix metalloproteinase activity; (2) abrogation of matrix degradation by 1,10-phenanthroline, a metalloproteinase inhibitor, and (3) degradation of purified type I collagen by PC3 cells and their conditioned medium. We demonstrate that human prostate cancer cells can directly degrade bone-related matrices and that matrix metalloproteinases have a role in this process.

Adenocarcinoma↗

PubMedDate not supplied

Regulation of tumor cell adhesion by intracellular 13-HODE: 15-HETE ratio.

We performed studies to determine whether tumor cells (TCs) produce 13-hydroxyoctadecadienoic acid (13-HODE) and 15-hydroxyeicosatetraenoic acid (15-HETE), and to determine the relationship between TC and endothelial cell (EC) 13-HODE and 15-HETE synthesis, and TC adhesion to ECs and their underlying extracellular matrix (ECM). We measured (1) the amounts and ratios of 13-HODE: 15-HETE in three different human TC lines and in three different murine TC lines under basal and stimulated conditions; and (2) the relationship between 13-HODE synthesis and cAMP levels in TCs and ECs. Under basal conditions, TCs produced both 13-HODE and 15-HETE, the intracellular ratios of which correlated with TC adhesivity. Stimulation of the TCs with the chemotactic tripeptide, N-formyl-methionyl-leucyl-phenylalanine, decreased 13-HODE synthesis, and increased 15-HETE synthesis and TC adhesion to ECs and to their ECM. Alternatively, enhancing 13-HODE synthesis in either TCs or ECs (by elevating the resting levels of intracellular cAMP) was associated with decreased TC adhesion to ECs and ECM. These results suggest that intracellular 13-HODE: 15-HETE ratio in TCs regulates TC adhesivity, and that an alteration in 13-HODE: 15-HETE ratio will markedly influence TC adhesion.

Animals↗