CXCR4的高量表現在HER2陰性之乳癌患者會促使淋巴結轉移的發生

Abstract

惡性腫瘤是台灣地區死亡原因的首位，一旦出現多處的轉移後，則不論使用何種藥物最終都無法控制。因此，癌細胞轉移的抑制對乳癌研究來說是個值得探討的方向。 腫瘤轉移的確切機制到目前為止，仍是未知。從臨床上的觀察，腫瘤發展到一定大小後，轉移的機率就增加。但是，到底轉移的機制是什麼？與腫瘤的生長有相關嗎？什麼樣的因子在控制著它？這些問題目前都還在研究當中。我們從長期觀察乳癌的病人中發現，如果有淋巴結的轉移，那麼之後有其他器官轉移的機率就高很多。因此，淋巴結的轉移可能就是這癌症轉移過程中的第一步，所以，若以淋巴結轉移為模型，就有可能可以進一步了解轉移的機轉。 腫瘤轉移的假說認為，可能有誘導的因子，才能帶領癌細胞進入到淋巴結甚至轉移至其他器官，亦即所謂種子與土壤（seed and soil）的觀念。目前已知可能相關的誘導因子就是stromal-derived factor 1（SDF-1），它與CXC chemokine receptor 4（CXCR4）是單一對應的蛋白質和接受體，在血液學的研究上，它可能擔任著帶領造血幹細胞回到骨髓的作用，因此腫瘤細胞的轉移可能也受該因子的操控。所以，我們假設，當腫瘤有較高的CXCR4表現時，腫瘤會產生淋巴結轉移的機率就會增加。研究的方法為，採取病人的乳癌腫瘤組織，做CXCR4的病理組織免疫染色的比較。依據病患臨床上淋巴結轉移的有無、腫瘤的大小、癌症分期、組織學、荷爾蒙接受體、HER2/neu來做相關的分析。假使假說是成立的，那麼有淋巴結轉移的患者，腫瘤組織會有CXCR4升高的情形。另外，HER2/neu及荷爾蒙接受體，對復發或轉移相關的因子是否藉由CXCR4來作用？與CXCR4的關係也是研究的重點之ㄧ。 收集了2006年一月至十二月在單一醫院內接受乳癌手術的患者。排除証實有遠處轉移、原位癌、腫瘤分期第四期、淋巴結轉移第三期，或者先接受前輔助化療的病患後，總共有80位患者做CXCR4的病理組織免疫染色，經病理科醫師判讀後，由影像分析軟體加以輔助，將染色結果量化後分為高表現組及低表現組，較為客觀的影像分析結果再進行分析比較。 結果顯示，CXCR4在大多數的乳癌組織都有表現，若劃分為高表現與低表現組後進行分析。則發現在全體病患的年齡、腫瘤大小、分期、淋巴結轉移的有無、淋巴結轉移的分期、荷爾蒙接受體，以及HER2/neu 接受體上均無差異。將條件限定在HER2/neu接受體陰性的情況下，則CXCR4的高表現與淋巴結轉移有相關，在統計上有意義。條件限定為荷爾蒙接受體表現為陽性時，CXCR4的高表現也與淋巴結轉移有關。 研究結果顯示，若HER2/neu陰性時，CXCR4的高表現與淋巴結轉移有關，且有統計上的意義，但是HER2/neu陽性時，CXCR4的高表現則會影響淋巴結轉移的程度，因個案數較少，無法呈現出統計上的意義。HER2/neu可能是乳癌轉移的一個重要因子，它與CXCR4之間也有著某種程度的相關，若Her2不表現時，CXCR4就會取而代之，成為轉移，甚至影響腫瘤惡性度的主要因子。 荷爾蒙接受體表現陽性時，CXCR4的過度表現可能也會促進淋巴結的轉移與其他研究部一致，需要進一步探討。大多數的研究，傾向荷爾蒙接受體會促進CXCR4的作用，但有些研究卻同時發現，CXCR4的表現雖然會提高，荷爾蒙卻也同時降低腫瘤細胞的移行能力。所以，荷爾蒙對轉移而言，尚未定論。臨床上長期服用荷爾蒙抑制劑確實能獲得較好的預後，可能是藉由抑制CXCR4的機轉所達成的，仍有待探討。

Purposes of the study: Lymph node metastasis is an important prognostic factor in breast cancer, and lymph node metastasis may be the initial step for further distal metastasis. Therefore, identifying the contributing factors of lymph node metastasis in breast cancer may be helpful to understand the mechanism of metastasis. CXC chemokine receptor 4（CXCR4）is a member of chemokine receptor which is mostly expressed in immune cells. However, many studies report the expression in cancer cell and the relationship between cancer metastasis and CXCR4 expression. So, our study is to identify the correlation between the CXCR4 expression and axillary lymph node metastasis. This study investigate the influence of hormone receptor and HER2/neu expression. Material and method: Patients who had distal metastasis, T4 or N3 stage breast cancer, predominant ductal carcinoma in situ, received neoadjuvant chemotherapy or no lymph node data available were excluded. Eighty breast cancer patients between January 2006 and December 2006 were enrolled. All patients received the breast surgery and axillary lymph node dissection or sentinel lymph node sampling. Breast cancer tissue fixed with formalin and embedded with paraffin was obtained and stained with anti-CXCR4 antibody (MAB170, R&D system). This immunohistochemistry (IHC) stain result was interpreted by expert pathologists and then analyzed by image analysis software (Image-pro plus Ver 5.1). According to image analysis result of IHC stain, we divide patients into two groups as CXCR4 high and low expression. The results with age, tumor size, lymph node metastasis, estrogen receptor (ER), progesterone receptor (PR), and HER2/neu were examined by chi-square or Fisher’s exact test. Result: There is no significant difference between CXCR4 expression and pathological characteristics. But, there is significant difference between CXCR4 expression and lymph node metastasis in HER2/neu negative (p = 0.04) and hormone receptor positive patients (p = 0.02 in ER and p = 0.03 in PR). Conclusion: Our finding is that CXCR4 high expression contributes to axillary lymph node metastasis, especially when HER2/neu is negative. In other words, CXCR4 may be an alternative pathway in tumor invasion and metastasis when HER2/neu is not working. Another result is that CXCR4 high expression in hormone receptor positive patient associate with axillary lymph node metastasis. However, the really relationship between hormone receptor and CXCR4 is not quite clear and it needs further study. But, if CXCR4 really has influence on hormone receptor positive cancer cell, maybe that’s the reason why we use hormone therapy could achieve better outcome.