Autocrine control of MTW9/PL2 rat mammary tumor cell growth
Abstract
Breast cancer is among a group of conditional neoplasias derived from endocrine target tissues and retain the ability to be influenced by their hormonal background. However, a gradual progression of breast neoplasias towards greater estrogen autonomy is known to occur in nearly all cases studied, seriously compromising the efficacy of hormone therapy. The mechanism responsible for the acquisition of estrogen autonomy was investigated in this dissertation, using the estrogen-responsive MTW9/PL rat mammary tumor cell line. In an attempt to select for highly estrogen-autonomous clonal variants these cells were passaged twice through castrated male rats for a total of 16 weeks, and the resulting cell line (MTW9B) was cloned. Unexpectedly, greater than 40% of the resulting clones were either estrogen-responsive or dependent in vivo, and along with further studies suggested that their survival depended on the residence of autonomous cells within the population via a non-host mediated mechanism. The possibility that the estrogen-dependent cells were supported by a growth factor activity secreted from autonomous cells was examined. In a serum-free defined medium (DDM-3) MTW9/PL2 (rederived MTW9/PL) cells were able to grow in the absence of exogenous growth factors for over ten days, at 60% to 80% of the serum-stimulated rate. Remarkably, a very potent, acid and heat labile, mitogenic activity was identified in DDM-3 conditioned by MTW9/PL2 cells when assayed on COMMA-D normal mouse mammary epithelial cells. This activity was not attributable to IGF-I, IGF-II, PDGF, EGF, TGF$\alpha$ or TGF$\beta$. The MTW9/PL2 derived growth factor activity was purified over 1000-fold from medium conditioned by cells in culture and from tumors in vivo. The physical properties of this activity(s) were very similar to those reported basic-fibroblast growth factor (bFGF), such as acid and heat lability, affinity to heparin, and competitive binding to FGF receptors. Consistent with their activities on normal mouse mammary cells, partially purified conditioned medium and tumor derived growth factor activity(s) and bFGF were active on MTB2 (estrogen-dependent clonally derived MTW9B) cells. These results support the notion that: (1) a bFGF-like activity is the major autocrine mitogen secreted by MTW9/PL2 rat mammary tumor cells, and is present in sufficient quantities to account for tumor epithelial and fibroblastic cell growth, and tumor angiogenesis, and (2) the progression to estrogen autonomy may be triggered by constitutive production of bFGF, or a bFGF-like molecule.
Subject Area
Biochemistry
Recommended Citation
Danielpour, David, "Autocrine control of MTW9/PL2 rat mammary tumor cell growth" (1987). Texas Medical Center Dissertations (via ProQuest). AAI8800593.
https://digitalcommons.library.tmc.edu/dissertations/AAI8800593