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Biomedical subjects

J Folkman

Publications and source records attributed to J Folkman.

At least 235 records · Page 13Linked to original sources
PubMed1982

Angiogenesis: initiation and control.

From in vivo experiments using new methods such as the rabbit cornea, it is now becoming clear that the growth of a capillary involves an ordered sequence of events that includes lysis of the basement membrane of a parent venule, directional migration of capillary endothelial cells toward the angiogenic stimulus, lumen formation, development of branches, and anastomosis of the tip of one tube with another to form a loop. It is also clear that diffusible angiogenic stimuli can be released not only from most solid tumors, but also from at least three non-neoplastic cells. These include activated macrophages, sensitized lymphocytes, and adipocytes. Other normal tissues can also stimulate angiogenesis, but the type of cell giving rise to the angiogenic stimulus is unknown, and the period of angiogenic stimulation is brief. With the recent ability to clone capillary endothelial cells and to carry them in long-term culture, it has been possible to further delineate the mechanism of capillary growth. In vitro studies have shown that the mast cell seems to behave as a helper cell for capillary endothelial cells, in some way speeding up their rate of directional migration. At this writing, heparin appears to be the principal mast cell factor responsible for this effect on capillary endothelial cells. One theoretical possibility is that mast cells may prepare the matrix, perhaps by slow release of heparin, so that capillary sprouts can more easily move through it toward their angiogenic target. While the study of angiogenesis as a phenomenon is still in an early phase, it has become possible, by using a combination of in vitro and in vivo techniques, to more thoroughly understand the initiation and control of capillary growth.

Adipose Tissue↗
PubMed1982

In vitro characteristics of endothelium from hemangiomas and vascular malformations.

Hemangiomas are vascular tumors characterized by rapid growth, increased endothelial turnover, and increased numbers of mast cells. Vascular malformations grow commensurately with the patient or expand secondary to hemodynamic alteration and are characterized by a normal endothelial cell cycle and normal numbers of mast cells. Operative specimens of vascular birthmarks were categorized as hemangiomas or malformations based on clinical history, light microscopic examination, and mast cell quantitation. The specimens were cultured in tumor-conditioned medium and plasma clot culture. Capillary endothelium derived from hemangioma specimens formed capillary tubes in tissue culture--"angiogenesis in vitro." Capillary endothelium from malformations was difficult to culture and was not observed to form tubules. Hemangioma specimens demonstrated rapid outgrowth of tubular structures from plasma clot cultures, whereas malformation tissue did not produce such outgrowth. These results indicate that hemangioma endothelium grows preferentially in culture in comparison with endothelium from vascular malformations. It suggests a biologic difference, which correlates with our previously proposed classification.

Adolescent↗
PubMed1981

Application of the biological principle of induced osteogenesis for craniofacial defects.

Demineralised bone implants were used for cranio-maxillofacial reconstruction and construction in 34 patients, 28 with congenital deformities and 6 with acquired defects. The patients' ages ranged from 15 months to 59 years (mean 18 years). In 33 cases, the implants were obtained from cadaver femurs; in 1 case, the implant was prepared from the patient's own skull. Early healing was assessed by clinical and radiographic examination and, when appropriate, by biopsy. Longer follow-up will be required to determine whether resorption has been avoided. The clinical advantages are rapid union, healing of large defects, avoidance of harvesting procedures, and the potentially unlimited supply of banked material.

Adolescent↗
PubMed1981

Interaction of serum and cell spreading affects the growth of neoplastic and non-neoplastic fibroblasts.

Both growth factor availability and cell-to-cell contact have been mechanisms used to explain cell growth regulation at high cell density. Recently Folkman and colleagues have shown that changes in cell shape, rather than cell-to-cell contact, can regulate the growth of fibroblasts. However, in those studies the relation between serum and shape regulation of growth was not studied, nor were neoplastic and non-neoplastic cells compared. In this report we have studied these aspects by varying cell spreading and serum concentration independently for 2 non-neoplastic and 3 neoplastic cell lines. Cell spreading (projected cell area) was controlled by decreasing the adhesiveness of tissue culture growth was measured as the increase in cell number/day. We have found that more spreading increased net growth of both neoplastic and non-neoplastic cells, while less spreading (toward rounded configuration) depressed growth. There were also quantitative differences between neoplastic and non-neoplastic cells. Neoplastic cells continued to grow under conditions of cell rounding, which completely prevented the growth of their non-neoplastic counterparts. Some neoplastic cells also tended to show little or no increase in net cell number for serum concentrations above 10% as cells became more spread; in contrast, all non-neoplastic cells grew more with increasing concentrations of serum as they became well spread. Thus, in normal cells, it appears that the sensitivity of cells to humoral factors is governed by cell spreading. This interaction between serum and cell shape is less prominent in some neoplastic cells.

Animals↗
PubMed1981

Inhibition of tumor growth, vascularization, and collagenolysis in the rabbit cornea by medroxyprogesterone.

Medroxyprogesterone, dexamethasone, or cortisone, locally applied in sustained release polymer to rabbit V2 carcinoma implanted in the rabbit cornea, blocked neovascularization and three-dimensional growth of the tumor. These hormones similarly prevented the vascular proliferative response to implants in the rabbit cornea of mouse B-16 melanoma and also the response to implants of polymer containing tumor extract with angiogenesis activity. The inhibitory responses were accompanied by considerable reduction in collagenolytic activity released into culture medium by explants of the two tumors and of the corneal region containing angiogenic hepatoma extract. Morphologic studies revealed extensive three-dimensional disruption of the compact laminated collagenous structure of the cornea by untreated V2 carcinoma. In the presence of hormone the tumor grew slowly as a noninvasive two-dimensional plaque limited to the narrow region of the insertion pocket in the cornea, with no obvious disturbance of structure elsewhere. Cortisone was much les effective than medroxyprogesterone or dexamethasone. Testosterone and estradiol had no effect on the three measured properties. The data suggest that local hormonal interference with neovascularization, collagenase production, and tumor growth can prevent neoplastic invasion and destruction of a dense collagenous connective tissue.

Animals↗
PubMed1981

Magnetic modulation of release of macromolecules from polymers.

Sustained-release systems were made by incorporating bovine serum albumin and magnetic steel beads in an ethylene-vinyl acetate copolymer matrix. When exposed to aqueous medium, the polymer matrix released the albumin slowly and continuously. Application of an oscillating magnetic field increased the release rate by as much as 100%. Intervals of 6-hr periods of magnetic exposure and nonexposure were alternated over a 5-day period, resulting in corresponding increases and decreases in release and establishing a pattern of modulated sustained release.

Animals↗
PubMed1981

Use of demineralized allogeneic bone implants for the correction of maxillocraniofacial deformities.

Two major problems in maxillocraniofacial surgery are the limited amount of fresh autogenous bone, the standard material for bone grafting, and the resorption of the grafted bone. Experimental studies with demineralized, devitalized bone matrix have shown induction of endochondral ossification. Fifty-five demineralized allogeneic implants have been used in 44 patients over the past two years for a variety of congenital (n = 37) and acquired (n = 7) defects. The allogeneic bone was obtained from cadavers, prepared as powders, chips or blocks, and was demineralized. After having been sterilized by irradiation, they were used to augment contour, fill defects, or construct bone within soft tissue. Of implanted sites that could be evaluated by physical examination, 31 of 31 were solid by three months. By radiographic examination three of 19 were healed by three months, and an additional 11 were positive by six months. Induced bone was seen in four of four biopsy specimens. Infection occurred in four of 44 patients (9%), comparable with conventional grafts. Implant resorption occurred in four instances. Allogeneic demineralized implants offer several advantages over conventional bone grafting, such as avoidance of a harvesting operation, ease of manipulation, and potentially unlimited material in banked form. In addition, healing by induced osteogenesis may bypass the resorption seen with healing of mineral-containing grafts.

Adolescent↗
PubMed1980

Angiogenesis in vitro.

Cloned capillary endothelial cells, cultured in tumour-conditioned medium, form capillary tubes. By light and electron microscopy these tubes resemble capillaries in vivo. This first demonstration of angiogenesis in vitro: (1) shows that all the information necessary to develop an entire capillary network in vitro is expressed by one cell type; (2) suggests a mechanism for lumen formation; and (3) offers a possibility of distinguishing between direct and indirect angiogenesis factors.

Angiogenesis Inducing Agents↗
PubMed1980

Transformed and neoplastic phenotype: reversibility during culture by cell density and cell shape.

The ability of parental and transformed mouse C3H (10T 1/2) cells to grow when held at a graded series of cell shapes (flat to round) was studied using substrata of decreasing adhesivity. The parental cells showed a decrease in growth when they reached the most rounded configurations. In contrast, transformed cells proliferated at the same rate regardless of cell shape. In addition, when transformed cells were serially passaged at low density on highly adhesive plastic, which maintained cells in a flat configuration, a reversion from the transformed phenotype to a non-transformed phenotype occurred with the concomitant return of growth control by cell shape. However, when transformed cells were passaged at low density on a substratum which prevented cell spreading, the reversion to the parental phenotype did not occur and the cells escaped the growth control of cell shape and remained tumorigenic. Thus, in this cell system it appears that a change in cell configuration can dictate whether or not the transformed and neoplastic phenotype will be expressed.

Animals↗
PubMed1980

Mast cell heparin stimulates migration of capillary endothelial cells in vitro.

Migration of capillary endothelial cells is an important component of angiogenesis in vivo. Increased numbers of mast cells have been associated with several types of angiogenesis. We have used a quantitative assay in vitro to demonstrate that mast cells release a factor that significantly increases bovine capillary endothelial cell migration. The factor is present in medium conditioned by mast cells as well as lysates of mast cells. The stimulatory effect of mast cells on migration is specific for capillary endothelial cells. Furthermore, mast cells have no mitogenic activity for capillary endothelial cells. Of all the secretory products of mast cells tested, only heparin stimulated capillary endothelial cell migration in vitro. Heparin preparations from a variety of sources stimulated capillary endothelial cell migration to the same degree but did not stimulate migration of several other cell types. The migration activity of heparin and mast cell conditioned medium was blocked by specific antagonists of heparin (protamine and heparinase), but not by chondroitinase ABC. The migration activity of mast cell conditioned medium was resistant to heat (100 degrees C) and incubation with proteolytic enzymes. These results suggest that the role of mast cells in angiogenesis may be to enhance migration of the endothelial cells of growing capillaries.

Animals↗
PubMed1980

Control of tumor growth in animals by infusion of an angiogenesis inhibitor.

Angiogenesis and tumor growth were inhibited in two different animal models by regional infusion of a partially purified cartilage extract. In rabbits bearing corneal implants of V2 carcinoma and receiving the inhibitor, vascular growth rates were < 3% of those in control animals receiving either Ringer's solution or bovine trypsin inhibitor (Trasylol). Subconjunctival B16 melanoma implants in mice receiving the inhibitor weight < 2.5% of implants in mice receiving Ringer's solution, Trasylol, or albumin. Histologic study of major organs and standard blood tests revealed no toxic effects in any of the animals. The inhibitor did not retard the growth of either tumor cell type in tissue culture at concentrations as high as 1 mg/ml. These results suggest that the cartilage factor does not interfere with the growth of the tumor cell population directly but that it prevents tumor growth by inhibiting angiogenesis.

Animals↗
PubMed1980

Angiogenic activity as a marker of neoplastic and preneoplastic lesions of the human bladder.

Angiogenic activity has been assessed in biopsy specimens from 49 patients with transitional cell carcinoma, benign prostatic hypertrophy and vesicoureteral reflux. Over 95% of the specimens containing malignant and premalignant transitional epithelium stimulated capillary proliferation on rabbit iris. In contrast, less than 10% of normal tissues had this effect. Sixty-one per cent of specimens with inflammatory round cells were angiogenic but this was reduced to 10% by preincubation with rabbit antihuman lymphocyte serum. Cystitis cystica also induced capillary proliferation even if incubated with the antilymphocyte serum. Angiogenic capacity may be an early marker of preneoplastic and neoplastic lesions of the human bladder.

Angiogenesis Inducing Agents↗
PubMed1980

One month of sustained release of insulin from a polymer implant.

Rats made diabetic with streptozotocin received a single subcutaneous implant of an insulin polymer pellet that released insulin continuously at approximately 2 U/day. Continuous normoglycemia was achieved for up to 1 mo. Mean glucose level for treated animals was 113 mg/dl as compared with 398 mg/dl for untreated diabetic controls. Diurnal blood glucose values for treated animals ranged from 71 to 116 mg/dl. Polyuria and glycosuria were corrected by the presence of the insulin + polymer. Treated animals gained weight normally and reached a mean weight of 350 g, whereas untreated control animals lost weight, to a mean of 150 g. When insulin + polymer preparations were periodically implanted and removed at 7-day intervals, normoglycemia was only associated with the presence of implants.

Animals↗
PubMed1980

Angiogenesis by capillary endothelial cells in culture.

Capillary endothelial cells cloned from bovine and human tissues were grown in long-term culture. In the presence of tumor-conditioned medium, capillary tubes formed when the cells became confluent. Each tube began as a longitudinal vacuole in one cell and then appeared to be extruded and connected from one cell to the next. Branches appeared, and a capillary network developed over a period of 2 to 3 weeks. By light and electron microscopy, the tubes were nearly identical to capillaries in vivo. These experiments: (1) Demonstrate angiogenesis in vitro; (2) Show that all the information necessary to develop an entire capillary in vitro can be expressed by one cell type; (3) Suggest a mechanism for lumen formation by capillaries in vivo; (4) Offer a possibility of distinguishing between direct and indirect angiogenesis factors.

Animals↗
PubMed1979

The effect of fibrin on cultured vascular endothelial cells.

The normal cobblestone monolayer architecture of cultured vascular endothelium becomes rapidly disorganized after contact of the cell layer with a fibrin clot. The cells of a confluent endothelial monolayer separate into individual migratory cells in 4--6 hr after contact with fibrin. The effect is reversible in that removal of the fibrin clot results in resumption of the normal morphology within about 2 hr. No other cell type tested exhibits the same change in organization when exposed to fibrin. A similar morphological change in endothelium does occur after the cell layer is overlaid with a collagen fibril gel but a gel of methylcellulose has no effect. It is proposed that the change in behavior of endothelial cells in response to contact with fibrin may represent a cellular component of fibrinolysis. The implications of this finding for the pathophysiology of disease states involving intravascular fibrin deposition are discussed.

Animals↗
PubMed1979

Bile duct enlargement by infusion of L-proline: potential significance in biliary atresia.

The normal signals of control of bile duct morphogenesis and growth are unknown. Consequently, aberrant development is poorly understood, as for example in those infants with biliary atresia or hypoplasia. A previous report by Isseroff et al., showed that a possible mechanism for the common bile duct enlargement by the parasite Fasciola hepatica was excess L-proline secreted by this parasite. This suggested to us that L-proline might be a specific growth factor for bile duct epithelium, and therefore possibly useful in the understanding and treatment of biliary maldevelopment. We now report an experimental study demonstrating the effect of L-proline on the normal biliary tree of the mouse. We also present a summary to date of an ongoing clinical restrospective study. These experimental findings suggest: (1) there may be a specific requirement for L-proline during the rapid growth of the biliary tract during neonatal life; (2) bile duct hypoplasia and atresia may result from a defect in proline metabolism; (3) proline administration during the early phase of biliary atresia may possibly be therapeutic.

Animals↗
PubMed1979

Long-term culture of capillary endothelial cells.

Capillary endothelial cells from rats, calves, and humans, have been carried in long-term culture. Bovine capillary endothelial cells have been cloned and maintained by serial passage for longer than 8 months. This prolonged culture was accomplished by using tumor-conditioned medium, gelatin-coated plates, and a method of enriching cells in primary culture. Cultured bovine capillary endothelial cells produce Factor VIII antigen and angiotensin-converting enzyme, but do not have Weibel-Palade bodies. Human cells do contain Weibel-Palade bodies. Capillary endothelial cells are distinguished from aortic endothelial cells by their requirement for conditioned medium. Bovine capillary endothelial cells in regular medium grow slowly with a mean doubling time of 67 hr and eventually die. In tumor-conditioned medium, these cells grow rapidly with a doubling time of 28 hr and continue to proliferate for as long as the tumor-conditioned medium is present. In contrast, bovine aortic endothelial cells grow as rapidly in regular medium as in tumor-conditioned medium. This method allows the production of pure capillary endothelial cells that may prove useful for studies of tumor angiogenesis, metastatic mechanisms, and the role of capillary endothelium in other pathologic states.

Adrenal Glands↗