System-wide analysis reveals a complex network of tumor-fibroblast interactions involved in tumorigenicity.
System-wide analysis reveals a complex network of tumor-fibroblast interactions involved in tumorigenicity.
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DOI：
10.1371/journal.pgen.1003789
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Powers RS
中科院分区：
文献类型：
--
作者：
Rajaram M;Li J;Egeblad M;Powers RS
许多成纤维细胞分泌的蛋白质促进肿瘤的形成，而癌细胞分泌的几种因素反过来又被提出诱导这些蛋白质。目前尚不清楚这些相互作用背后是否有单一的主导路径，或者它们是否涉及多条并行作用的路径。在这里，我们通过比较基因组分析确定了42个由乳腺癌细胞诱导的成纤维细胞分泌因子。为了确定哪些组分在促进肿瘤形成方面是有效的，我们选择了五个具有代表性的成纤维细胞分泌因子进行体内分析。我们发现，大多数(五分之三)在促进致瘤性方面发挥了同样重要的作用，有趣的是，每一种都对肿瘤微环境有不同的影响。具体地说，成纤维细胞分泌的两性调节素促进了乳腺癌细胞的存活，而趋化因子CCL7刺激了肿瘤细胞的增殖，而CCL2促进了天然免疫细胞的渗透和血管生成。另外两个被测试的因素对成纤维细胞促进肿瘤生长的能力有轻微的(CCL8)或最小的(STC1)显著影响。通过同时靶向癌细胞上的成纤维细胞分泌的双调节蛋白和CCL7受体来测试成纤维细胞和癌细胞之间平行相互作用的重要性，这比单独阻断任何一条途径都要有效得多。我们通过测试乳腺癌细胞产生的单一因子在多大程度上能够诱导关键的成纤维细胞分泌蛋白质，进一步探索了平行相互作用的概念。我们发现，虽然单一因素可以诱导基因的一个子集，但即使是因素的组合也不能诱导具有重要功能的成纤维细胞分泌蛋白的全部谱系。总之，这些结果描绘了一个复杂的肿瘤-成纤维细胞相互作用的网络，这些相互作用平行地促进肿瘤的致瘤性，并表明有效的抗间质治疗策略将需要多靶点。人们对通过靶向在肿瘤微环境中发挥支持作用的非肿瘤细胞来治疗癌症的方法越来越感兴趣。沿着这些路线受到相当大关注的一种非癌症细胞是癌症相关成纤维细胞，它可以促进肿瘤的形成和肿瘤的生长。已有多项研究表明，抑制单个成纤维细胞基因或蛋白质会显著降低成纤维细胞的肿瘤支持功能。从制定治疗策略的角度来看，目前尚不清楚的是，迄今为止发现的几种不同的重要因素是否反映了促进肿瘤发生的多种成纤维细胞因子的要求，或者它是否反映了这些不同研究中使用的上皮性癌细胞和成纤维细胞的多样性。在这里，我们直接使用成纤维细胞和乳腺癌上皮细胞的单一系统来解决这个问题。重要的是，我们发现多种成纤维细胞因子确实是促进肿瘤发生所必需的，而且它们对肿瘤微环境有不同的影响。此外，我们发现抑制多种成纤维细胞分泌因子比阻断单个因子更有效。这些结果表明，成纤维细胞和癌细胞通过多个平行的途径发挥作用，有效的抗间质治疗策略需要多靶点。
Many fibroblast-secreted proteins promote tumorigenicity, and several factors secreted by cancer cells have in turn been proposed to induce these proteins. It is not clear whether there are single dominant pathways underlying these interactions or whether they involve multiple pathways acting in parallel. Here, we identified 42 fibroblast-secreted factors induced by breast cancer cells using comparative genomic analysis. To determine what fraction was active in promoting tumorigenicity, we chose five representative fibroblast-secreted factors for in vivo analysis. We found that the majority (three out of five) played equally major roles in promoting tumorigenicity, and intriguingly, each one had distinct effects on the tumor microenvironment. Specifically, fibroblast-secreted amphiregulin promoted breast cancer cell survival, whereas the chemokine CCL7 stimulated tumor cell proliferation while CCL2 promoted innate immune cell infiltration and angiogenesis. The other two factors tested had minor (CCL8) or minimally (STC1) significant effects on the ability of fibroblasts to promote tumor growth. The importance of parallel interactions between fibroblasts and cancer cells was tested by simultaneously targeting fibroblast-secreted amphiregulin and the CCL7 receptor on cancer cells, and this was significantly more efficacious than blocking either pathway alone. We further explored the concept of parallel interactions by testing the extent to which induction of critical fibroblast-secreted proteins could be achieved by single, previously identified, factors produced by breast cancer cells. We found that although single factors could induce a subset of genes, even combinations of factors failed to induce the full repertoire of functionally important fibroblast-secreted proteins. Together, these results delineate a complex network of tumor-fibroblast interactions that act in parallel to promote tumorigenicity and suggest that effective anti-stromal therapeutic strategies will need to be multi-targeted. There is increasing interest in developing methods to treat cancer by targeting non-cancer cells that play supportive roles in the tumor microenvironment. One type of non-cancer cell that has received considerable attention along these lines is cancer-associated fibroblasts, which can promote tumor formation and tumor growth. There have been several studies showing that inhibition of individual fibroblast genes or proteins dramatically reduces the tumor supportive function of fibroblasts. From the perspective of developing a therapeutic strategy, what remains unclear is whether the several different important factors discovered to date reflect the requirement of a multitude of fibroblast factors to promote tumorigenicity, or whether it reflects the diversity of the epithelial cancer cells and fibroblasts used in these different studies. Here, we addressed this question directly using a single system of fibroblasts and breast cancer epithelial cells. Importantly, we found that a multitude of fibroblast factors are indeed required to promote tumorigenicity, and that they have different effects on the tumor microenvironment. Furthermore, we found that inhibiting multiple fibroblast-secreted factors is more efficacious than blocking individual factors. These results suggest that fibroblasts and cancer cells act through multiple parallel pathways and that effective anti-stromal therapeutic strategies will need to be multi-targeted.
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DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
11.2
作者：
Cheng, Nikki;Chytil, Anna;Mosesi, Harold L.
通讯作者：
Mosesi, Harold L.
内在遗传特征决定了成纤维细胞的肿瘤修饰能力：基质金属蛋白酶-3 5A/5A基因型可增强乳腺癌细胞的侵袭。
DOI：
10.1186/bcr1775
发表时间：
2007
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Holliday DL;Hughes S;Shaw JA;Walker RA;Jones JL
通讯作者：
Jones JL
影响因子：
6.4
作者：
Jung, Da-Woon;Che, Zhong Min;Kim, Jin
通讯作者：
Kim, Jin
影响因子：
50.3
作者：
Allinen, M;Beroukhim, R;Polyak, K
通讯作者：
Polyak, K