McLeskey S W, Kurebayashi J, Honig S F, Zwiebel J, Lippman M E, Dickson R B, Kern F G
Lombardi Cancer Research Center, Georgetown University Medical Center, Washington, DC 20007.
Cancer Res. 1993 May 1;53(9):2168-77.
Successful antiestrogen treatment in patients with tamoxifen-responsive breast tumors is often followed by an outgrowth of tumors cells that are antiestrogen resistant, implying that estrogen-dependent tumors can become estrogen-independent. In an effect to mimic this progression, we have transfected fibroblast growth factor 4 into MCF-7 cells, a human breast carcinoma cell line that is estrogen-dependent for growth in nude mice. This transfection results in cell lines that form progressively growing, metastatic tumors when injected s.c. into untreated or tamoxifen-treated ovariectomized nude mice. In contrast to the parental cell line, growth of transfected cells in ovariectomized nude mice is stimulated by tamoxifen treatment and inhibited by estrogen treatment of the mice. Parental MCF-7 cells were transfected with an expression vector for beta-galactosidase, conferring the ability to convert the chromogenic substrate, 5-bromo-4-chloro-3-indoyl-beta-galactoside, to a blue color and allowing the detection of their presence within tumors developing after coinoculation with fibroblast growth factor 4-transfected cells. The fibroblast growth factor 4-transfected cells could support growth and metastasis of the beta-galactosidase-expressing parental cell line when both lines were coinjected into the same site in untreated or tamoxifen-treated, ovariectomized mice. These data suggest a possible role for fibroblast growth factors in the progression of breast tumors to an estrogen-independent, antiestrogen-resistant, metastatic phenotype. They also support a role for paracrine factors in mixed populations of tumor cells of differing states of malignant progression.
在对他莫昔芬敏感的乳腺肿瘤患者中，成功的抗雌激素治疗后常常会出现抗雌激素耐药的肿瘤细胞生长，这意味着雌激素依赖性肿瘤可以转变为雌激素非依赖性肿瘤。为了模拟这种进展过程，我们将成纤维细胞生长因子4转染到人乳腺癌细胞系MCF-7中，该细胞系在裸鼠体内的生长依赖雌激素。这种转染产生的细胞系，当皮下注射到未处理或经他莫昔芬处理的去卵巢裸鼠体内时，会形成逐渐生长的转移性肿瘤。与亲代细胞系不同，去卵巢裸鼠体内转染细胞的生长受到他莫昔芬治疗的刺激，而受到小鼠雌激素治疗的抑制。用β-半乳糖苷酶表达载体转染亲代MCF-7细胞，使其具有将生色底物5-溴-4-氯-3-吲哚-β-半乳糖苷转化为蓝色的能力，从而能够在与成纤维细胞生长因子4转染细胞共接种后形成的肿瘤中检测到它们的存在。当将这两种细胞系同时注射到未处理或经他莫昔芬处理的去卵巢小鼠的同一部位时，成纤维细胞生长因子4转染细胞能够支持表达β-半乳糖苷酶的亲代细胞系的生长和转移。这些数据表明，成纤维细胞生长因子在乳腺肿瘤进展为雌激素非依赖性、抗雌激素耐药的转移表型过程中可能发挥作用。它们还支持旁分泌因子在不同恶性进展状态的肿瘤细胞混合群体中的作用。
