Abstract
Tumors are composed of the tumor cells and the surrounding microenvironment. Both are closely interwoven and interact by a complex and multifaceted cross-talk which plays an integral part in tumor initiation, growth, and progression. Dro1/Ccdc80 has been shown to be a potent suppressor of colorectal cancer and ubiquitous inactivation of Dro1/Ccdc80 strongly promoted colorectal carcinogenesis in ApcMin/+ mice and in a chemically-induced colorectal cancer model.The aim of the present study was to investigate whether Dro1/Ccdc80’s tumor suppressive function is tumor-cell-autonomous. Expression of Dro1/Ccdc80 in cancer cells had no effect on both colon tumor development in ApcMin/+ mice and formation of xenograft tumors. In contrast, DRO1/CCDC80 loss in the microenvironment strongly increased tumor growth in xenograft models, inhibited cancer cell apoptosis, and promoted intestinal epithelial cell migration. Moreover, stromal Dro1/Ccdc80 inactivation facilitated formation of intestinal epithelial organoids. Expression analyses showed Dro1/Ccdc80 to be significantly down-regulated in murine gastric cancer associated fibroblasts, in ApcMin/+ colon tumor primary stromal cells and in microdissected stroma from human colorectal cancer compared to normal, non-tumor stroma. Our results demonstrate epithelial derived DRO1/CCDC80 to be dispensable for intestinal tissue homeostasis and identify Dro1/Ccdc80 as tumor suppressor in the tumor microenvironment.
Highlights
Dro1/Ccdc80 has been identified as a tumor suppressor of colorectal, thyroid, and ovarian cancer [1–3]
In the present study we demonstrate that tumor suppression by Dro1/Ccdc80 is not tumor-cell-autonomous but is mediated by the tumor microenvironment
Colon tumor development in ApcMin/+ mice as well as formation of xenograft tumors was unaffected by Dro1/Ccdc80 expression in cancer cells, suggesting epithelial derived DRO1/CCDC80 to be dispensable for intestinal tissue homeostasis
Summary
Dro1/Ccdc has been identified as a tumor suppressor of colorectal, thyroid, and ovarian cancer [1–3]. Dro1/Ccdc suppresses anchorage independent growth [2], inhibits migration of cancer cells [4] and induces sensitization to detachment-induced apoptosis [2]. Down-regulation of Dro1/Ccdc has been shown in primary human colorectal, thyroid, and melanoma skin cancer [1, 2, 4, 5]. In ApcMin/+ mice ubiquitous inactivation of Dro1/Ccdc results in early death, a significant increase in the colonic tumor load, and the regular www.oncotarget.com formation of adenocarcinoma in the colon [1]. Loss of DRO1/CCDC80 increases multiplicity of preneoplastic aberrant crypt foci and colonic tumors in carcinogeninduced colon carcinogenesis and promotes formation of colon adenocarcinoma during inflammation-driven carcinogenesis [6]. In colon tumors from ApcMin/+ mice loss of DRO1/CCDC80 induces ERK1/2 phosphorylation and leads to c-MYC oncogene activation [1]. The Dro1/ Ccdc tumor suppressor function has been reviewed in detail in [7]
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