Cornil I, Theodorescu D, Man S, Herlyn M, Jambrosic J, Kerbel R S
Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Canada.
Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6028-32. doi: 10.1073/pnas.88.14.6028.
It is known from a variety of experimental systems that the ability of tumor cells to grow locally and metastasize can be affected by the presence of adjacent normal tissues and cells, particularly mesenchymally derived stromal cells such as fibroblasts. However, the comparative influence of such normal cell-tumor cell interactions on tumor behavior has not been thoroughly investigated from the perspective of different stages of tumor progression. To address this question we assessed the influence of normal dermal fibroblasts on the growth of human melanoma cells obtained from different stages of tumor progression. We found that the in vitro growth of most (4 out of 5) melanoma cell lines derived from early-stage radial growth phase or vertical growth phase metastatically incompetent primary lesions is repressed by coculture with normal dermal fibroblasts, suggesting that negative homeostatic growth controls are still operative on melanoma cells from early stages of disease. On the other hand, 9 out of 11 melanoma cell lines derived from advanced metastatically competent vertical growth phase primary lesions, or from distant metastases, were found to be consistently stimulated to grow in the presence of dermal fibroblasts. Evidence was obtained to show that this discriminatory fibroblastic influence is mediated by soluble inhibitory and stimulatory growth factor(s). Taken together, these results indicate that fibroblast-derived signals can have antithetical growth effects on metastatic versus metastatically incompetent tumor subpopulations. This resultant conversion in responsiveness to host tissue environmental factors may confer upon small numbers of metastatically competent cells a growth advantage, allowing them to escape local growth constraints both in the primary tumor site and at distant ectopic tissue sites.
从多种实验系统可知，肿瘤细胞在局部生长和转移的能力会受到相邻正常组织和细胞的影响，特别是间充质来源的基质细胞，如成纤维细胞。然而，从肿瘤进展的不同阶段的角度来看，这种正常细胞与肿瘤细胞相互作用对肿瘤行为的比较影响尚未得到充分研究。为了解决这个问题，我们评估了正常真皮成纤维细胞对从肿瘤进展不同阶段获得的人黑色素瘤细胞生长的影响。我们发现，与正常真皮成纤维细胞共培养会抑制大多数（5个中的4个）源自早期放射状生长期或垂直生长期、无转移能力的原发性病变的黑色素瘤细胞系的体外生长，这表明负性稳态生长控制在疾病早期的黑色素瘤细胞上仍然起作用。另一方面，发现11个源自晚期有转移能力的垂直生长期原发性病变或远处转移灶的黑色素瘤细胞系中有9个在真皮成纤维细胞存在的情况下持续受到刺激而生长。有证据表明，这种有差异的成纤维细胞影响是由可溶性抑制性和刺激性生长因子介导的。综上所述，这些结果表明成纤维细胞衍生的信号对有转移能力和无转移能力的肿瘤亚群可能具有相反的生长作用。对宿主组织环境因素反应性的这种转变可能赋予少数有转移能力的细胞生长优势，使它们能够在原发性肿瘤部位和远处异位组织部位逃脱局部生长限制。
