Dabbous M K, North S M, Haney L, Nicolson G L
Department of Biochemistry, University of Tennessee, Memphis.
Cancer Res. 1988 Dec 1;48(23):6832-6.
The collagenolytic responses of normal rat skin fibroblasts (NRS-F) and rat mammary MTLn3 tumor-derived fibroblasts (Ln3-F) were examined following exposure to rat macrophage (M phi-CM)- and lymphocyte (LYM-CM)-conditioned culture medium and/or tumor cell-conditioned medium. Alveolar, intratumoral, and peritoneal macrophages were prepared from mammary adenocarcinoma-bearing rats, as were the peritoneal lymphocytes. Incubation of the two fibroblast populations with LYM-CM produced a 10- and 7-fold stimulation of collagenolytic activity by NRS-F and Ln3-F cells, respectively. Similarly, exposure of NRS-F and Ln3-F fibroblasts to peritoneal M phi-CM produced a 7- and 4-fold increase in the expression of collagenolytic activity, respectively. Conditioned medium from MTLn2 tumor cells also stimulated the collagenolytic expression of both fibroblast populations. Incubation of tumor-associated Ln3-F or NRS-F fibroblasts with MTLn2 tumor cell-conditioned medium enhanced fibroblast collagenolytic activity approximately 20 and 17 times, respectively. When M phi-CM and LYM-CM were further "conditioned" by a subsequent incubation with MTLn2 tumor cells, each stimulated the expression of collagenolytic activity by both fibroblast populations and this was especially pronounced (120-fold increase) in the response of Ln3-F to LYM-CM further conditioned by MTLn2 tumor cells. The conditioned media derived from M phi, LYM, and MTLn2 tumor cells with or without trypsin activation contained low levels of interstitial-type collagenolytic activity which made no significant contribution to the collagenolytic activity of the stimulated fibroblasts. Some collagenase inhibitory activity, however, was detected in the M phi-CM, suggesting that the actual stimulation of collagenolysis by host fibroblasts is underestimated. We conclude that macrophages, lymphocytes, and tumor cells all have the potential to produce stimulatory factor(s) which enhance the collagenolytic activity of normal fibroblast populations. This study provides further evidence of the multifactorial control of collagenase production and supports the concept that host cell-tumor cell interactions can enhance the expression of collagenolytic enzymes.
在分别暴露于大鼠巨噬细胞（M phi-CM）、淋巴细胞（LYM-CM）条件培养基和/或肿瘤细胞条件培养基后，检测正常大鼠皮肤成纤维细胞（NRS-F）和大鼠乳腺MTLn3肿瘤来源的成纤维细胞（Ln3-F）的胶原酶解反应。从荷乳腺腺癌大鼠中制备肺泡巨噬细胞、肿瘤内巨噬细胞和腹腔巨噬细胞，以及腹腔淋巴细胞。用LYM-CM培养这两种成纤维细胞群体时，NRS-F和Ln3-F细胞的胶原酶解活性分别受到10倍和7倍的刺激。同样，将NRS-F和Ln3-F成纤维细胞暴露于腹腔M phi-CM中，胶原酶解活性的表达分别增加了7倍和4倍。MTLn2肿瘤细胞的条件培养基也刺激了这两种成纤维细胞群体的胶原酶解表达。用MTLn2肿瘤细胞条件培养基培养肿瘤相关的Ln3-F或NRS-F成纤维细胞，可使成纤维细胞的胶原酶解活性分别提高约20倍和17倍。当M phi-CM和LYM-CM通过随后与MTLn2肿瘤细胞共培养进一步“条件化”时，二者均刺激了这两种成纤维细胞群体的胶原酶解活性表达，这在Ln3-F对经MTLn2肿瘤细胞进一步条件化的LYM-CM的反应中尤为明显（增加了120倍）。来自M phi、LYM和MTLn2肿瘤细胞的条件培养基，无论有无胰蛋白酶激活，均含有低水平的间质型胶原酶解活性，对受刺激的成纤维细胞的胶原酶解活性无显著贡献。然而，在M phi-CM中检测到了一些胶原酶抑制活性，这表明宿主成纤维细胞对胶原酶解的实际刺激作用被低估了。我们得出结论，巨噬细胞、淋巴细胞和肿瘤细胞都有可能产生刺激因子，增强正常成纤维细胞群体的胶原酶解活性。本研究进一步证明了胶原酶产生的多因素控制，并支持宿主细胞-肿瘤细胞相互作用可增强胶原酶表达的概念。
