中醫大 李文華校長: tumor‐draining LNs (TDLNs)促進乳癌惡性度 (Treg-->TGF‐β1--> IL‐17RB)

癌症生物學腫瘤抑製劑先驅─中國醫藥大學李文華校長 獲頒世界科學院院士榮銜(中央社訊息服務20180131 13:29:29)國際知名的癌症生物學專家、中國醫藥大學李文華校長，長期投入癌症遺傳基因領域研究表現出類拔萃有卓越貢獻，榮獲國際學術組織「世界科學院」（The World Academy of Sciences, TWAS）2018年度新任院士，稱得上實至名歸，全校師生和校友都倍感歡欣榮耀。中國醫藥大學校長李文華(Dr. Wen-Hwa Lee)是癌症生物學腫瘤抑製劑的先驅，於1986年首次發現確定人類第一個腫瘤抑制基因RB，表明該基因的重新引入抑制了腫瘤，並闡明了兩種乳腺癌易感基因BRCA-1和2在調節基因組穩定性方面的功能，改變了生醫界對癌症成因的觀念，開啟了癌症研究的新方向，更帶給癌症病患治療新希望。癌症遺傳基因領域一代巨擘李文華校長，在1987年獲選諾貝爾醫學獎候選人，1994年獲選為中研院第20屆生命科學組院士，美國國家發明家學會(NAI)2014年發明家院士，曾獲得台灣傑出乳腺癌研究獎，美國歐文分校艾哈邁克克拉克傑出研究獎等殊榮。李文華院士帶領的基因體研究團隊，新近發表「調節性免疫T細胞及脂肪細胞反助乳癌細胞壯大、提供乳癌治療更充分資訊」研究成果，證實剃除腫瘤引流淋巴結(TDLN)的免疫細胞Tregs，便可抑制該淋巴結內癌細胞IL-17RB基因的活化情形，並降低癌細胞的毒性；若將TDLN以手術移除，乳癌細胞擴散的機率將大幅降低。此研究對於在診治上不確定是否要切除淋巴結的醫師而言，提供了明確指標，同時確認發展IL-17RB抗體是治療乳癌的新方向。不僅如此，該研究團隊的另一項研究則指出，除了免疫細胞外，乳癌患者的脂肪細胞亦是助長乳癌細胞壯大的利器。研究發現，脂肪細胞分泌的β-HB，可促進MCT2基因高表現的乳癌腫瘤增生。因此，以MCT2做為標的進行治療或許可成為乳癌治療的另一道曙光！成立於1983年的國際學術組織「世界科學院」（The World Academy of Sciences, TWAS）公布的2018年度新任院士(結構、細胞、分子生物類)，中國醫藥大學校長李文華院士雀屏中選，卓越研究成果獲得高度評價與肯定。「世界科學院」TWAS旨在協助發展中國家從事科學研究與開發應用，目前有來自90個國家1千2百多位院士；當選該科學院院士或獲獎，不僅代表學者個人的成就，更代表所屬國家對於各會員國家科學之持續關懷與付出。訊息來源： 中國醫藥大學

TGF‐β1 secreted by Tregs in lymph nodes promotes breast cancer malignancy via up‐regulation of IL‐17RB / EMBO Mol Med. 2017 Dec; 9(12): 1660–1680. Lymph node (LN) metastasis is commonly associated with systemic distant organ metastasis in human breast cancer and is an important prognostic predictor for survival of breast cancer patients. However, whether tumor‐draining LNs (TDLNs) play a significant role in modulating the malignancy of cancer cells for distant metastasis remains controversial. Using a syngeneic mouse mammary tumor model, we found that breast tumor cells derived from TDLN have higher malignancy and removal of TDLNs significantly reduced distant metastasis. Up‐regulation of oncogenic Il‐17rb in cancer cells derived from TDLNs contributes to their malignancy. TGF‐β1 secreted from regulatory T cells (Tregs) in the TDLNs mediated the up‐regulation of Il‐17rb through downstream Smad2/3/4 signaling. These phenotypes can be abolished by TGF‐β1 neutralization or depletion of Tregs. Consistently, clinical data showed that the up‐regulation of IL‐17RB in cancer cells from LN metastases correlated with the increased prevalence of Tregs as well as the aggressive growth of tumors in mouse xenograft assay. Together, these results indicate that Tregs in TDLNs play an important role in modulating the malignancy of breast cancer cells for distant metastasis. Blocking IL‐17RB expression could therefore be a potential approach to curb the process.

Introduction: Cancer metastasis is a complex process involving tumor microenvironment and systemic changes (Joyce & Pollard, 2009). It has been reported that both blood circulation and lymphatic system can mediate systemic metastasis in human carcinoma (Nathanson et al, 2015). In breast cancer, mounting evidence indicates that the initial sites of metastasis are the regional lymph nodes (LNs), while spread of cancer cells goes through lymphatic system (Leong, 2004; Viehl et al, 2011; Podgrabinska & Skobe, 2014). Clinical studies have demonstrated a highly significant association between LN metastasis and distant metastasis in breast cancer patients (Abner et al, 1998; Rouzier et al, 2002; Nathanson et al, 2009). The increase in lymphangiogenesis, up‐regulation of chemokines and cytokines, and remodel of high endothelial venules are observed in the TDLNs which facilitates cancer cell entry into lymphatic system (Pereira et al, 2015). While LNs are initial metastatic sites of breast cancer, the biological influence on cancer cells in the LN microenvironment remains elusive. It is noted that the LNs could induce anti‐tumor immune response to retard tumor spread (Kim et al, 2006). Tumor‐specific T cells are activated by antigen‐presenting dendritic cells (DCs) in the LNs which are able to restrict metastatic outgrowth of disseminated cancer cells (Chamoto et al, 2006; Eyles et al, 2010). However, in breast cancer patients, altered compositions of immune cells and decreased anti‐tumor immune response in TDLNs have been reported (Kohrt et al, 2005; Matsuura et al, 2006). For example, recruitment of immunosuppressive cells such as regulatory T cells (Tregs), which suppress cytotoxic CD8+ T cells, has been observed in LNs with metastasized cancer cells (Mansfield et al, 2009; Nakamura et al, 2009; Faghih et al, 2014). Moreover, alteration of immune cell profile in the TDLNs has been suggested to be a good predictor of relapse‐free and disease‐free survival in early stage breast cancer patients (Kohrt et al, 2005; Nakamura et al, 2009). In addition to the change in immune cell composition, elevated levels of immunosuppressive cytokines such as TGF‐β1, IL‐10, and GM‐CSF have been observed in the TDLNs of patients with breast cancer and other carcinoma diseases(Dalal et al, 1993; Leong et al, 2002; Lee et al, 2005). These immunosuppressive cytokines may increase Treg differentiation and influence DC maturation in the TDLNs (Munn & Mellor, 2006). Alteration of immune cell composition and enrichment of immunosuppressive cytokines in the TDLNs implicate that a permissive microenvironment is created for cancer cell to survive and expand (Swartz & Lund, 2012).Evidences from clinical trials suggest that metastasis to LNs reflects tumor aggressiveness but not distant organ metastasis (Gervasoni et al, 2007; Leong & Tseng, 2014). Such argument, however, cannot explain the strong association between LN metastasis and distant metastasis in breast cancer patients (Rouzier et al, 2002; Ran et al, 2010). The experimental mouse model demonstrated that the stimulation of lymphangiogenesis by breast cancer cells secreted growth factors is important for cancer metastasis to distant organ metastasis (Hirakawa et al, 2007; Wang et al, 2012).Thus, how LNs modulate cancer cells gaining malignancy to metastasize to distant organs remains to be resolved. In this communication, we found that in the syngeneic mouse mammary tumor models, breast cancer cells derived from the TDLNs exhibited higher malignancy assayed by tumorigenic and metastatic activities. Furthermore, distant metastasis was significantly reduced when the TDLNs were removed at early time point. Elevated prevalence of Tregs in the TDLNs had a prominent effect on promoting cancer malignancy. The enhancement of cancer malignancy was due to the up‐regulation of an oncogenic receptor, Il‐17rb, by Treg‐secreted TGF‐β1.Blocking this TGF‐β1/TGFR paracrine signaling abolished Il‐17rb induction as well as inhibited tumorigenic activities of cancer cells. These observations were validated using a cohort of human breast cancer cells derived from either primary tumors or LN metastasis of the same patients, supporting a significant role of TDLNs in modulating cancer cells gained malignancy.

乳癌細胞如何壯大中研院團隊解謎團 2017-10-25 作者 記者李虎門 中央研究院院士，同時擔任中國醫藥大學校長李文華所帶領的團隊，分別針對微環境內兩種免疫細胞及脂肪細胞進行深入研究，找出助長乳癌細胞壯大的機制，為乳癌治療提供更充分的資訊。首先，在乳癌模式小鼠的淋巴結中，若剃除腫瘤引流淋巴結的免疫細胞Tregs，便可抑制該淋巴結內癌細胞IL-17RB基因的活化情形，並降低癌細胞的毒性。若將乳癌模式小鼠的腫瘤引流淋巴結以手術移除，乳癌細胞擴散的機率就會大幅降低。此一研究結果對於在診治上不確定是否要切除淋巴結的醫師而言，提供了明確的指標，同時也確認發展IL-17RB抗體是治療乳癌可行的方向之一。該研究成果已於本(10)月9日發表於《EMBO分子醫學》 (EMBO Molecular Medicine) 期刊。當乳癌細胞轉移到「腫瘤引流淋巴結(tumor-draining lymph nodes, TDLN)」時，醫師即可藉此瞭解腫瘤惡化的程度，但究竟是否有必要進行手術治療？ 論文第一作者，中研院基因體中心博士後研究人員黃世嘉表示，在黑色素瘤的診療上，目前已有數據證明，切除腫瘤附近的淋巴結，對預後有正向關聯，但在乳癌治療卻尚未有定論。甚至有些人認為，乳癌細胞在淋巴結內，並無特別的影響力，而這個轉移的資訊，目前僅用於判定癌症的期別為主。在淋巴結這個微環境內，其實充滿了各種免疫細胞，對於癌細胞似乎並不是一個安身立命的地方，但為什麼癌細胞仍會選擇移動至此呢？研究團隊為一探究竟，與臺大醫學院多位醫師合作展開研究後發現，在各式各樣的免疫細胞裡，有一種「調節性免疫T細胞 (Regulatory T cells簡稱Tregs) 」，作為一個矯正型的角色，當其他免疫細胞過度活化時，Tregs則會分泌TGF-β1分子進行控制與調節。然而，當乳癌細胞進到淋巴結時，Tregs所分泌的TGF-β1分子將反而助長乳癌細胞內IL-17RB基因的活化，進而增強乳癌細胞的毒性，而IL-17RB正是李文華實驗室長期研究的一個基因。人體全身除了負責輸送血液的血管之外，淋巴管也是一個遍布全身且整體連通的系統，而淋巴管因為不像血管有來自心臟的壓力，所以流速較慢，更適合細胞通過。這對於蠢蠢欲動於開疆闢土、持續擴散的癌細胞，是個絕佳的通道；在淋巴管內，癌細胞可以穩定流動，更可在「驛站」休息，而這個休息點即為淋巴結。在醫學上，連通腫瘤的淋巴結，便是「腫瘤引流淋巴結」。研究團隊已證實，腫瘤引流淋巴結內的免疫細胞會分泌TGF-β1分子，該分子會促使腫瘤引流淋巴結內的乳癌細胞增加IL-17RB基因的表現，進而增加了乳癌細胞擴散的能力。TDLN內的Tregs分泌TGF-β1活化乳癌細胞的IL-17RB基因，因而促進乳癌細胞的擴散能力。另一方面，團隊的研究也指出，除了免疫細胞外，乳癌患者的脂肪細胞亦是助長乳癌細胞壯大的利器。臨床觀察指出，乳房較大的女性，罹患乳癌的風險較高，顯示脂肪細胞在乳癌細胞微環境的重要性。 研究團隊取得乳癌患者的脂肪組織後，針對乳癌細胞與脂肪細胞的關係進行研究並發現，脂肪細胞透過分泌β-HB，促進MCT2高表現的乳癌腫瘤增生，該研究於2017年3月發表於《自然通訊》(Nature Communications) 期刊。根據該文章第一作者黃俊凱敘述，他們的研究與先前研究不同點在於，直接從乳癌患者的脂肪細胞角度切入，找出一個表現於乳癌細胞膜上，同時在脂肪細胞互動上扮演重要角色的基因MCT2。而在臨床中，MCT2的高表現量伴隨著較差的預後。MCT2的主要功能在於傳遞，且位於乳癌細胞膜上的閘口，在功能上可以讓β-羥基丁酸 (β-HB）分子進出。經由研究發現，脂肪細胞分泌的β-HB，可促進MCT2高表現的乳癌腫瘤增生。也因此，脂肪組織在MCT2高表現的乳癌患者，反倒成為幫助乳癌壯大的角色。或許，以MCT2做為標的，可成為乳癌治療的另一道途徑。