A consequence of ionizing radiation injury to normal tissue is production of a tumor bed effect (TBE) defined by altered growth of neoplasms in the damaged environment. Mechanistically, the TBE is thought to be a consequence of the inability of radiation-damaged vasculature to meet the demands of an expanding neoplastic population, and infers that tumor cells must compete for limited resources in a more hostile, stressful environment. We propose that this change in the micro-environment leads to an alteration of expression of growth factors involved in tumor-directed angiogenesis: specifically TGF-a and TGF-b. To test this hypothesis, we will use a battery of 9 human colon tumor cells, which show different levels of expression of, or response to, the polypeptide growth factors TGF-a and TGF-b. Solid xenograft tumors will be grown in nude mice and in either unirradiated or irradiated (20 Gy, 250 kVp x-rays) normal tissue. Levels of TGF-a and TGF-b mRNA as well as possible gene amplification will be assayed in sol id tumors as a function of tumor size using Northern and Southern blot techniques. These levels will be compared to levels of these cell lines growing in vitro. As these growth factors may act in both autocrine and paracrine fashion, we will also assay the numbers of receptors on these 9 human colon tumor lines in vitro using 125 I-labeled TGF-a and TGF-b. To quantitate the actual production of TGF-a and TGF-b, bioassay techniques will be used with these cell lines growing in vitro (specifically stimulation of NRK fibroblast growth and production of gel contraction in human foreskin fibroblast-loaded collagen gels). The results from these studies will be correlated with in vivo levels of TBE expression determined with volumetric techniques; with the extent of intratumoral hypoxia, with the numbers of host cells in tumors, and with flow cytometric data. With this information, we should be able to gain clinically relevant information on autocrine/paracrine regulation of neoplastic growth in normal or damaged microenvironments. Such data may then provide insight into why recurrent tumors are clinically more refractory to retreatment. If growth factor levels are increased, this may provide a relatively specific """"""""target"""""""" for therapy (i.e.,by use of a blocking antibody which might be radioactively labeled).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA050350-01
Application #
3194762
Study Section
Radiation Study Section (RAD)
Project Start
1989-08-01
Project End
1992-07-31
Budget Start
1989-08-01
Budget End
1990-07-31
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Brown University
Department
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Leith, J T; Michelson, S (1995) Levels of selected growth factors in viable and necrotic regions of xenografted HCT-8 human colon tumours. Cell Prolif 28:279-86
Leith, J T; Michelson, S (1995) Secretion rates and levels of vascular endothelial growth factor in clone A or HCT-8 human colon tumour cells as a function of oxygen concentration. Cell Prolif 28:415-30
Michelson, S; Leith, J T (1995) Interlocking triads of growth control in tumors. Bull Math Biol 57:345-66
McCarty 3rd, L P; Karr, S M; Harris, B Z et al. (1995) Comparison of basic fibroblast growth factor levels in clone A human colon cancer cells in vitro with levels in xenografted tumours. Br J Cancer 72:10-6
Leith, J T (1994) Enhancement of thermal sensitivity of xenografted human DLD-2 tumors by administration of basic fibroblast growth factor. Radiat Res 138:139-42
Michelson, S; Leith, J T (1994) Dormancy, regression, and recurrence: towards a unifying theory of tumor growth control. J Theor Biol 169:327-38
Leith, J T; Quaranto, L; Padfield, G et al. (1993) Radiobiological studies of PC-3 and DU-145 human prostate cancer cells: x-ray sensitivity in vitro and hypoxic fractions of xenografted tumors in vivo. Int J Radiat Oncol Biol Phys 25:283-7
Leith, J T; Michelson, S (1993) Effects of administration of basic fibroblast growth factor on hypoxic fractions in xenografted DLD-2 human tumours: time dependence. Br J Cancer 68:727-31
Leith, J T; Padfield, G; Michelson, S (1992) Effects of partial hepatectomy on the growth characteristics and hypoxic fractions of xenografted DLD-2 human colon cancers. Radiat Res 132:263-8
Leith, J T; Papa, G; Quaranto, L et al. (1992) Modification of the volumetric growth responses and steady-state hypoxic fractions of xenografted DLD-2 human colon carcinomas by administration of basic fibroblast growth factor or suramin. Br J Cancer 66:345-8

Showing the most recent 10 out of 19 publications