癌症纖維母細胞（cancer-associated fibroblast，簡稱CAF）已被研究報導會分泌高量的促炎性細胞激素。這些促炎性細胞激素，包含白細胞介素-1（IL-1）、白細胞介素-6（IL-6）和白細胞介素-8（IL-8），可協助腫瘤細胞的增殖、血管生成和入侵。然而，在癌症發展的過程中，纖維母細胞如何變成具有高度活性的促炎性纖維母細胞，其機制仍不清楚。本篇研究藉由共同培養的方式，發現經乳癌細胞共同培養的乳腺正常組織纖維母細胞（normal tissue-associated fibroblast，簡稱NAF）會持續性地表現高量的促炎性細胞激素，包括IL-1a、IL-1b、IL-6及IL-8，顯示其具有促炎性纖維母細胞的特徵。IL-1a和IL-1b曾分別被研究指出在IL-6和IL-8的誘導過程中扮演重要的角色，因此本研究測試了以下的假說：乳癌細胞可藉由IL-1a或 IL-1b的訊息傳導路徑誘導正常纖維母細胞之IL-6和IL-8的表現。本研究利用IL-1a的抗體處理經乳癌MDA-MB-468細胞共同培養後的正常纖維母細胞，以去除其IL-1a的活性，發現可完全抑制纖維母細胞中所提升之IL-8的表現，也可部份地抑制IL-1b和IL-6的表現。用IL-1b的抗體處理，則無此效果。進一步的實驗發現，以抗體抑制IL-1a的活性也會減少癌症纖維母細胞之IL-1b、IL-6和IL-8的表現。這些結果顯示IL-1a可誘導癌症纖維母細胞中IL-1b、IL-6和IL-8的表現。以基質細胞中的癌症纖維母細胞（cancer-associated fibroblast，簡稱CAF）已被研究報導會分泌高量的促炎性細胞激素。這些促炎性細胞激素，包含白細胞介素-1（IL-1）、白細胞介素-6（IL-6）和白細胞介素-8（IL-8），可協助腫瘤細胞的增殖、血管生成和入侵。然而，在癌症發展的過程中，纖維母細胞如何變成具有高度活性的促炎性纖維母細胞，其機制仍不清楚。本篇研究藉由共同培養的方式，發現經乳癌細胞共同培養的乳腺正常組織纖維母細胞（normal tissue-associated fibroblast，簡稱NAF）會持續性地表現高量的促炎性細胞激素，包括IL-1a、IL-1b、IL-6及IL-8，顯示其具有促炎性纖維母細胞的特徵。IL-1a和IL-1b分別被研究指出在IL-6和IL-8的誘導過程中扮演重要的角色，因此本研究測試了以下的假說：乳癌細胞可藉由IL-1a或 IL-1b的訊息傳導路徑誘導正常纖維母細胞之IL-6和IL-8的表現。本研究利用IL-1a抗體處理經乳癌MDA-MB-468細胞共同培養後的正常纖維母細胞，以去除其IL-1a活性，發現可完全抑制纖維母細胞中所提升之IL-8的表現，也可部份地抑制IL-1bIL-6的表現。用IL-1b抗體處理，則無此效果。進一步的實驗發現，以抗體抑制IL-1a活性也會減少癌症纖維母細胞之IL-1bIL-6和IL-8的表現。這些結果顯示IL-1a誘導癌症纖維母細胞中IL-1bIL-6和IL-8的表現。以基質細胞中的 Cancer-associated fibroblasts (CAFs) have been shown to secrete high levels of proinflammatory cytokines. These proinflammatory cytokines, such as interleukin-6 (IL-6) and IL-8, were reported to assist cancer cell proliferation, angiogenesis and invasion. However, the mechanisms by which fibroblasts become proinflammatory ones during cancer progression are still not known. In this study, I found that through co-culturing with breast cancer cells, breast normal tissue-associated fibroblasts (NAFs) obtained persistent activity for expressing high levels of proinflammatory factors, including IL-1a, IL-1b, IL-6 and IL-8. IL-1a and IL-1b were respectively reported to play a role in induction of IL-6 and IL-8, so I tested the hypothesis that breast cancer cells might induce IL-6 and IL-8 expression in NAFs via an IL-1a or IL-1b signaling pathway. By using an IL-1a neutralizing antibody, I found that abolishment of IL-1a activity completely repressed the enhanced IL-8 expression and partially reduced the enhanced IL-1b and IL-6 expression in NAFs that were pre-cocultured with breast cancer MDA-MB-468 cells. However, an IL-1b neutralizing antibody had no effect on the expression of these cytokines. Furthermore, the treatment of an IL-1a neutralizing antibody also reduced the enhanced IL-1b, IL-6 and IL-8 expression in CAFs. These results suggested that IL-1a may mediate induction of IL-1b, IL-6 and IL-8 expression in cancer-associated fibroblasts. An IL-1a signaling pathway in stromal cells may be a target for prevention of breast cancer development and progression.
