乳腺癌患者中有大約20%會發生遠處轉移，科學家希望阻止癌細胞轉移或一旦發生轉移立即治療，這樣能夠提高患者的生存率。
2017年1月31日，美國《細胞·報告》正式發表密歇根大學的研究報告，對乳腺癌的原發灶和轉移灶進行分析，以了解乳腺癌細胞為何轉移。
該研究在腫瘤微環境中發現一種促進乳腺癌細胞擴散的蛋白質，該蛋白質屬于酪氨酸激酶受體家族，該家族的受體蛋白質在許多種癌癥中發揮作用，科學家也一直在開發靶向這類蛋白質的抑制劑分子。
該研究從患者發生轉移的病變部位獲取組織樣本，并對腫瘤周圍的細胞進行分析。腫瘤微環境中存在多種細胞類型，包括免疫細胞、脈管細胞、基質干細胞。
結果發現，基質干細胞能夠影響轉移灶，基質干細胞表面的膠原受體：盤基蛋白域受體2（DDR2）能夠為乳腺癌細胞開辟道路幫助其擴散，并通過激活信號促進癌細胞生長。當DDR2出現在細胞上，能夠觀察到癌細胞、基質干細胞、膠原有序高效地形成一個轉移灶；當敲除細胞上的DDR2，癌細胞和膠原就會變得雜亂無章，影響癌細胞的遷移和轉移灶的形成。
隨后，該研究又對DDR2敲除小鼠進行了分析，這些小鼠體內形成的轉移腫瘤更少，亦未出現相關細胞的有序排列跡象。
因此，該研究發現DDR2介導了基質干細胞和癌細胞之間的交流，當抑制基質干細胞上的這種受體，就會欺騙癌細胞，導致相關細胞不會發生有序排列，癌細胞也不會遷移，也就不會有效地形成轉移灶，表明DDR2是一個潛在的治療靶點。
Cell Rep. 2017 Jan 31;18(5):1215-1228.
Mesenchymal Stem Cell-Induced DDR2 Mediates Stromal-Breast Cancer Interactions and Metastasis Growth.
Gonzalez ME, Martin EE, Anwar T, Arellano-Garcia C, Medhora N, Lama A, Chen YC, Tanager KS, Yoon E, Kidwell KM, Ge C, Franceschi RT, Kleer CG.
University of Michigan, Ann Arbor, MI 48109, USA.
Highlights
MSCs are present in human breast cancer metastatic microenvironment
DDR2 regulates MSC phenotype, collagen deposition function, and migration
DDR2 activation in breast cancer depends on stroma-derived DDR2
Inhibition of DDR2 in the tumor microenvironment reduces metastasis
Increased collagen deposition by breast cancer (BC)-associated mesenchymal stem/multipotent stromal cells (MSC) promotes metastasis, but the mechanisms are unknown. Here, we report that the collagen receptor discoidin domain receptor 2 (DDR2) is essential for stromal-BC communication. In human BC metastasis, DDR2 is concordantly upregulated in metastatic cancer and multipotent mesenchymal stromal cells. In MSCs isolated from human BC metastasis, DDR2 maintains a fibroblastic phenotype with collagen deposition and induces pathological activation of DDR2 signaling in BC cells. Loss of DDR2 in MSCs impairs their ability to promote DDR2 phosphorylation in BC cells, as well as BC cell alignment, migration, and metastasis. Female ddr2-deficient mice homozygous for the slie mutation show inefficient spontaneous BC metastasis. These results point to a role for mesenchymal stem cell DDR2 in metastasis and suggest a therapeutic approach for metastatic BC.
KEYWORDS: DDR2; EZH2; breast cancer; collagen; discoidin domain receptor; mesenchymal stem cell; metastasis; microenvironment; phosphorylated DDR2; tumor stroma
PMID: 28147276
DOI: 10.1016/j.celrep.2016.12.079
