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D R Senger

Publications and source records attributed to D R Senger.

At least 55 records · Page 3Linked to original sources
PubMed1989

Pathogenesis of tumor stroma generation: a critical role for leaky blood vessels and fibrin deposition.

Tumor stroma formation results from the interaction of tumor cells and their products with the host and certain of its normal defense mechanisms, particularly the clotting and fibrinolytic systems. It is a process in which tumor cells render local venules and veins hyperpermeable with the result that fibrinogen and other proteins extravasate and clot, forming an extravascular crosslinked fibrin gel. Coagulation is mediated by an interaction between extravasated plasma clotting factors and tumor-associated and perhaps other tissue procoagulants. Parallel activation of the fibrinolytic system leads to substantial fibrin turnover, but fibrin nonetheless accumulates in amounts, variable from tumor to tumor, that are sufficient to provide a provisional stroma. This provisional stroma imposes on tumor cells a structure that persists even as tumor cells multiply and as the fibrin provisional stroma is replaced by mature connective tissue. The provisional fibrin stroma also serves to regulate the influx of macrophages, and perhaps other inflammatory cells, but at the same time, and in ways that are not fully understood, facilitates the inward migration of new blood vessels and fibroblasts, integral components of mature tumor stroma. Ascites tumors differ from solid tumors in that fibrin gel is not ordinarily deposited in body cavities and, as a result, there is no provisional stroma to impose an initial structure. Tumor stroma generation resembles the process of wound healing in many respects. However, it differs in the mechanism of its initiation, and in the apparent lack of a role for platelets. It also differs fundamentally in that invading tumor cells continually render new vessels hyperpermeable to plasma, thus perpetuating the cycle of extravascular fibrin deposition. In this sense, tumors behave as wounds that do not heal. Largely neglected in this review has been discussion of the numerous cytokines, mitogens, and growth factors that are widely believed to play important roles in tumor angiogenesis and wound healing; i.e., PDGF, FGF, EGF, TGF alpha, TGF beta, TNF, interferons, etc. This omission has been intentional, and for two reasons. First, these cytokines have already received considerable attention [100,123-128]. Second, it is not yet clear how closely the actions of these molecules, as described in vitro, relate to their functions in vivo. At present we are deluged with a surfeit of factors that have the capacity to induce new blood vessel formation in angiogenesis assays; these factors include not only peptides but lipids and even ions [126,129-131].(ABSTRACT TRUNCATED AT 400 WORDS)

Blood Coagulation↗
PubMed1988

Secreted phosphoproteins associated with neoplastic transformation: close homology with plasma proteins cleaved during blood coagulation.

We have previously demonstrated that a wide variety of rodent and human tumor cells secrete markedly elevated levels of a transformation-related phosphoprotein with a molecular weight (depending on animal species) of 58,000 to 69,000. With antibody raised to the tumor-secreted phosphoprotein (rat), we have now identified an antigenically related protein in normal rat and human plasma. The rat plasma protein and the rat tumor-secreted phosphoproteins comigrated on polyacrylamide gels and were identically cleaved during blood coagulation as well as by purified thrombin. Mouse macrophages expressed a similar or identical phosphoprotein suggesting that monocytic cells may be a source of the normal plasma protein. Consistent with elevated secretion of this protein by tumor cells, plasma and sera from cancer patients contained elevated levels of this protein, raising the possibility that this circulating marker may prove useful for monitoring tumor burden. Amino acid sequence derived from the amino terminus of the rat tumor phosphoprotein indicates that it is distinct from previously sequenced proteins, but that it may be related to protein-tyrosine kinases encoded by viral and proto-onc genes.

Amino Acid Sequence↗
PubMed1988

T24 human bladder carcinoma cells with activated Ha-ras protooncogene: nontumorigenic cells susceptible to malignant transformation with carcinogen.

A comparative analysis of T24 human bladder carcinoma cells and N-methyl-N'-nitro-N-nitrosoguanidine (MeNNG)-transformed derivatives (MeNNG-T24 cells) revealed the following: (i) The presence of an activated c-Ha-ras gene (in the absence of the normal allele) is insufficient to confer upon T24 cells a tumor-associated phenotype. (ii) MeNNG-transformed T24 cells not only acquire tumor-associated (in vitro) traits (growth in soft agar and rhodamine retention) but, are highly tumorigenic in nude mice. (iii) It is possible to render T24 cells tumorigenic by chemical transformation; therefore, the reason that T24 cells lack tumorigenicity is not because of possible incompatibilities between these cells and nude mice but, in fact, because T24 cells are not malignant. (iv) The loss of expression of a transformation-related Mr 67,000 phosphoprotein by MeNNG-T24 cells after explantation of these cells from nude mouse tumors to in vitro culture indicates that culture conditions can be responsible for rapid phenotypic conversion of human tumor cell lines.

Animals↗
PubMed1986

A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines.

We have previously reported that rodent tumor cell lines secrete a potent vascular permeability factor with a molecular weight of 34,000-42,000 (Senger et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science (Wash. DC), 219: 983-985, 1983). This tumor-secreted vascular permeability factor (VPF) causes a rapid and completely reversible increase in microvascular permeability in the species (guinea pig or rat) from which the tumors were derived without causing mast cell degranulation or endothelial cell damage or exciting an inflammatory cell infiltrate. This VPF may be responsible, at least in part, for the increased permeability which is commonly displayed by solid and ascites tumor vessels. We have now examined 7 human tumor cell lines and have determined that 5 of them also secrete this same VPF. Antibody raised to guinea pig line 10 VPF neutralized more than 90% of the vascular permeability-increasing activity secreted by these 5 human tumor lines. Furthermore, VPFs from both guinea pig and human tumor sources bound to and were eluted similarly from immobilized heparin and comigrated identically on sodium dodecyl sulfate-polyacrylamide gels. Finally, 2 tumorigenic (in nude mice) human cell lines were found to secrete at least 14-fold more VPF than their directly matched, nontumorigenic counterparts, suggesting that elevated expression of this permeability factor may correlate with neoplastic transformation. These data suggest that a broad spectrum of tumor cells from several species, including humans, secretes a highly conserved molecule that enhances local vascular permeability and that this function may be important for tumor growth.

Animals↗
PubMed1985

Regulation of extravascular coagulation by microvascular permeability.

Extravascular coagulation is a prominent feature of such important pathological processes as cellular immunity and neoplasia and has been thought to result from procoagulants associated with the inflammatory or tumor cells peculiar to these entities. It was found that increased microvascular permeability alone is sufficient to induce equivalent extravascular coagulation in several normal tissues. The results indicate that saturating levels of procoagulant are present even in normal tissues and that microvascular permeability is a rate-limiting step in extravascular coagulation.

Animals↗
PubMed1985

Secreted phosphoprotein markers for neoplastic transformation of human epithelial and fibroblastic cells.

A wide variety of rodent tumor cells of both fibroblastic and epithelial origins secrete a major transformation-related phosphoprotein with a molecular weight of approximately 62,000. Tumorigenic cells, regardless of the transforming agent, secrete 10-fold or more of this 32P-labeled protein as compared with their nontumorigenic counterparts. In this study we have extended these previous findings to tumorigenic human cells of diverse origins (both sarcomas and carcinomas). Metabolic labeling of cells with [32P]orthophosphate and immunoprecipitation with antibody specifically directed against the rat transformation-dependent secreted phosphoprotein have been used to identify antigenically related human phosphoproteins (Mr 66,000-69,000). Of the 14 human cell lines examined, all 8 of the lethal tumorigenic cell populations secreted these phosphoproteins either in continuous culture or as fresh explants from nude mice while the six nonmalignant cell lines did not (tumorigenicity in all cases was assayed in nude mice). Included in our study were three tumorigenic human cell lines (two sarcomas, one carcinoma), each with a matched, nontumorigenic control. The very close correlation between secretion of these phosphoproteins and the tumor cell phenotype of both rodents and humans raises the possibility that they may be important for tumor growth in vivo.

Animals↗
PubMed1983

A secreted phosphoprotein marker for neoplastic transformation of both epithelial and fibroblastic cells.

A wide variety of virally and spontaneously transformed fibroblasts secrete a major transformation-related phosphoprotein with a molecular weight (MW), depending on the species of origin, of about 62,000 (62K). Markedly elevated extracellular levels of this major 32P-labelled protein are not simply linked to exponential growth but instead are associated directly with transformation. The phosphoprotein is not antigenically related to p60src, p60c-src or simian virus 40 (SV40) non-viral T antigen, and it is further distinguishable from SV40 non-viral T antigen (pp 53) on the basis of its electrophoretic mobility. In this study we have compared a variety of normal and transformed epithelial cells for secretion of this 32P-labelled protein and have found that this marker distinguishes neoplastic from preneoplastic and normal mouse mammary epithelium and also identifies highly tumorigenic cells derived from guinea pig bile duct epithelium and rat liver epithelium. Because the classical phenotypic properties commonly associated with transformation of fibroblasts cannot be generally used to discriminate tumorigenic from non-tumorigenic epithelial cells, this phosphoprotein, which identifies tumorigenic cells of both fibroblastic and epithelial origin, is likely to be of particular importance.

Acetoxyacetylaminofluorene↗
PubMed1983

Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid.

Tumor ascites fluids from guinea pigs, hamsters, and mice contain activity that rapidly increases microvascular permeability. Similar activity is also secreted by these tumor cells and a variety of other tumor cell lines in vitro. The permeability-increasing activity purified from either the culture medium or ascites fluid of one tumor, the guinea pig line 10 hepatocarcinoma, is a 34,000- to 42,000-dalton protein distinct from other known permeability factors.

Animals↗
PubMed1983

Fibrin as a component of the tumor stroma: origins and biological significance.

An association between cancer and the coagulation system was suggested by Trousseau more than a century ago and initial reports of fibrin deposition in the stroma of solid tumors date back some 25 years. However, the validity and generality of these observations have only quite recently been established, and their implications for an understanding of tumor biology, metastasis, and therapy are only now coming to be appreciated by investigators in the mainstream of cancer research. This article reviews the current status of fibrin's role in the biology of tumor growth, considering in turn: (1) the evidence that fibrin is present in tumors, the nature of such fibrin, and its relation to plasma fibronectin; (2) the mechanisms by which fibrin may come to be deposited in tumors; and (3) the potential biological and medical significance of tumor-associated fibrin deposition and degradation. Among the last are such important possibilities as a barrier function to the immune response and possible roles in angiogenesis, desmoplasia, and metastasis.

Animals↗
PubMed1983

Complex regulation of fibronectin synthesis by cells in culture.

We have studied the biosynthesis of fibronectin by NIL8 hamster embryo cells in various stages of growth. Pulse labeling with [35S]methionine, immunoprecipitation, electrophoresis, and autoradiography were employed to compare fibronectin synthesis by cells in subconfluent monolayers, confluent monolayers, and "aged" postquiescent monolayers. We have determined that fibronectin synthesis is proportionally low while cells are subconfluent, rises to maximal levels at confluence but just prior to quiescence, and then declines with increasing culture age in quiescent cultures. Furthermore, when cells are stimulated to grow, the effects on rates of fibronectin synthesis depend on the prior history of the cells; freshly confluent cells stimulated to grow show reductions in rate of fibronectin synthesis, whereas aged postquiescent cultures show increases in this rate. These results are in contrast to those on the rates of synthesis of other proteins (including the precursor to the C3 component of complement), which strictly correlate with quiescence and do not decline significantly with culture age postconfluence. We have also determined that the microheterogeneity of pulse-labeled fibronectin differs between exponentially growing and quiescent cells and that it becomes less heterogeneous once cells are quiescent. We conclude that the microheterogeneity of pulse-labeled fibronectin and the proportionate amount of total fibronectin synthesized both depend on growth state prior to the entry of cells into quiescence and that they depend on culture age thereafter.

Animals↗
PubMed1979

Transformed mammalian cells secrete specific proteins and phosphoproteins.

We have examined the proteins secreted into the growth medium by normal and transformed cells. Transformed cell lines from several mammalian species all secrete proteins in the 58,000 dalton molecular weight range. These proteins are all immunologically related and are secreted at low levels or not at all by the parental normal cell lines. Secretion of the 58K proteins occurs with either DNA or RNA virus transformation and with spontaneous transformation. The transformed cells also secrete phosphoproteins in the same size range, but these are immunologically distinct from the 58K proteins mentioned above. The sizes of the phosphoproteins are species-specific and unrelated to the transforming virus. Incubation of conditioned media from transformed cell cultures with gamma-32P-ATP labels phosphoproteins of the same sizes, indicating the presence in the media of both protein kinase and substrate. All three properties (58K protein, phosphoprotein, in vitro phosphorylation) are closely correlated with transformation in cells transformed by temperature-sensitive viruses. The biological implications of these results remain unknown, but the results may be relevant to recent data on the (phospho)proteins and protein kinase encoded by RNA tumor viruses and the molecular basis of the transformed phenotype.

Cell Line↗
PubMed1978

C3 component of complement secreted by established cell lines.

The hamster cell line NIL8 secretes the C3 component of complement as well as collagenous molecules and fibronectin (LETS protein). The C3 is found in the culture medium as a disulfidebonded complex of two polypeptides of 130,000 daltons (alpha) and 65,000 daltons (beta). The secreted C3 can be quantitatively cleaved to C3b and further cleaved by C3 inactivators. The activation of C3 to C3b is promoted by zymosan or by antibody-coated erythrocytes, demonstrating participation in both the classical and alternative complement pathways. The availability of this culture system has enabled us to show that C3 is synthesized as a 185,000 dalton precursor (proC3) which is biologically inactive and becomes cleaved to active C3. Some other established cell lines (NIL1 and BALB/c 3T3) also secrete C3, but some others do not.

Animals↗