人類鱗狀上皮細胞癌與癌症相關纖維母細胞之交互作用

Abstract

口腔癌在台灣高居國人癌症死因第六位，在男性中癌症致死率更高居第四；口腔癌具有高度侵犯轉移的能力，下頷骨的破壞發生常被作為判斷鱗狀細胞癌的惡性程度和預後。在腫瘤惡化的過程中，癌症細胞和間質細胞的交互作用扮演重要角色。近年來，各項研究已經逐漸了解癌細胞與癌症相關纖維母細胞之間的關係，其中纖維母細胞的活化狀態會影響腫瘤相關發炎反應的調控。本研究的主軸為觀察人類鱗狀上皮細胞癌與癌症相關纖維母細胞之交互作用。目前已知癌細胞藉由分泌因子促進腫瘤惡化；然而，纖維母細胞表現調控癌症進程的因子仍然不清楚。白血球趨化激素CXCL1可以促進乳癌以及大腸直腸癌的轉移並且會在活化的纖維母細胞中表現，因此，我們假設CXCL1可以在口腔癌之癌相關纖維母細胞中表現並促進口腔癌轉移。分析人類纖維母細胞與癌症相關纖維母細胞的特性中，顯示α-smooth muscle actin 以及發炎相關細胞激素IL-6, IL-8, MCP-1，在癌症相關纖維母細胞的表現量大於正常纖維母細胞，並且癌症相關纖維母細胞促進口腔癌細胞移行的能力比正常纖維母細胞顯著。藉由CXCL1的中和抗體以及其接受器CXCR2的拮抗劑處理，發現CXCL1在纖維母細胞促進的癌細胞移行扮演重要的角色。我們也進一步發現由CXCL1重組蛋白刺激的癌細胞會增加基質金屬蛋白酵素 (matrix metalloproteinase)-2 (MMP-2)的mRNA表現量，但不影響 MMP-1。另ㄧ方面，口腔癌細胞及口腔癌相關纖維母細胞的分泌因子，可以促進老鼠巨噬細胞產生蝕骨細胞分化所需之轉錄因子NFATc1。這些研究結果指出正常纖維母細胞受癌細胞刺激後會表現出癌症相關纖維母細胞的特性，包含發炎相關細胞激素表現與促進癌細胞移行能力。纖維母細胞藉由分泌因子CXCL1調控口腔癌惡化，而經由癌細胞活化的纖維母細胞會增加CXCL1表現量；並且，口腔癌細胞的分泌因子具有促進蝕骨細胞分化的潛力，進一步促進腫瘤生長之發炎行為環境。

Oral squamous cell carcinoma (OSCC), is the fourth common male cancer and the sixth leading cause of cancer death in Taiwan known for its potent activity in local bone invasion/osteolysis, which has a critical influence on the prognosis. Interaction between tumor and stroma cells are important in tumor progression. The effect of tumor cell-secreted factor on metastasis is well established, however little is known about the effect of factors secreted by CAFs on tumor progression. CXCL1, the chemokine involved in promoting of colorectal cancer migration, and can be expressed in activated fibroblast. Therefore, we hypothesis that CXCL1 can be expressed in OSCC-related CAFs and promote tumor migration. Fibroblast activation marker α-smooth muscle actin and proinflammatory cytokine including IL-6, IL-8 and MCP-1 are highly expressed in CAFs than normal gingival fibroblast. The migration of OSCC was enhanced by secreted factors from resting or activated CAFs and inhibited by CXCL1 neutralizing antibody and CXCR2 antagonist SB225002. Moreover, matrix metalloproteinase (MMP)-2 mRNA, but not MMP-1 was elevated in SAS cells in response to CXCL1. On the other hand, the osteoclastogenic factor nuclear factor of activated T-cells c1 can be induced by OSCC or CAFs secreted factors in Raw 264.7 cells. Taken together, CAFs can release some factors including CXCL1 to modulate the tumor migration and osteoclast differentiation.