Hhip regulates tumor-stroma-mediated upregulation of tumor angiogenesis

다국어 초록 (Multilingual Abstract)

Tumor growth is governed by the coordinated action of various types of cells that are present in the tumor environment. Fibroblasts, which constitute a major fraction of the stroma, participate actively in various signaling events and regulate tumor development and metastasis. The Hedgehog (Hh) pathway plays an important role in promoting tumor malignancy via fibroblasts; however, the role of hedgehog interacting protein (hhip; inhibitor of Hh pathway) in tumor growth is poorly understood. Here we implanted B16F10 tumors in hhip+/ − mice to study the tumor growth characteristics and the vascular phenotype. Furthermore, the mechanism involved in the observed phenomena was explored to reveal the role of hhip in tumor growth. The tumors that were implanted in hhip+/ − mice exhibited accelerated growth and increased tumor angiogenesis. Although we observed a decrease in hypoxia, blood vessels still had abnormal phenotype. We found that increased Hh signaling in tumor fibroblasts induced a high expression of vascular endothelial growth factor (VEGF), which subsequently resulted in an increased proliferation of endothelial cells. Thus, the heterozygous knockdown of hhip in mice could affect Hh signaling in tumor fibroblasts, which could cause the increased production of the growth factor VEGF. This signaling, via a paracrine effect on endothelial cells, increased tumor vascular density.

참고문헌 (Reference)

1 Chuang PT, "Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein" 397 : 617-621, 1999

2 Choe C, "Tumor-stromal interactions with direct cell contacts enhance motility of non-small cell lung cancer cells through the hedgehog signaling pathway" 33 : 3715-3723, 2013

3 Taniguchi H, "Transcriptional silencing of hedgehog-interacting protein by CpG hypermethylation and chromatic structure in human gastrointestinal cancer" 213 : 131-139, 2007

4 Lauth M, "Think inside the BOCs : a mechanism underlying medulloblastoma progression" 31 : 1-2, 2014

5 Shahi MH, "The sonic hedgehog-GLI1 signaling pathway in brain tumor development" 16 : 1227-1238, 2012

6 Kharaishvili G, "The role of cancer-associated fibroblasts, solid stress and other microenvironmental factors in tumor progression and therapy resistance" 14 : 41-, 2014

7 Koyama-Nasu R, "The critical role of cyclin D2 in cell cycle progression and tumorigenicity of glioblastoma stem cells" 32 : 3840-3845, 2013

8 Hui M, "The Hedgehog signalling pathway in breast development, carcinogenesis and cancer therapy" 15 : 203-, 2013

9 Gupta S, "Targeting the Hedgehog pathway in cancer" 2 : 237-250, 2010

10 Orimo A, "Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion" 121 : 335-348, 2005

11 Mao Y, "Stromal cells in tumor microenvironment and breast cancer" 32 : 303-315, 2013

12 Kobune M, "Stromal cells expressing hedgehog-interacting protein regulate the proliferation of myeloid neoplasms" 2 : e87-, 2012

13 Alphonso A, "Stromal cells and integrins : conforming to the needs of the tumor microenvironment" 11 : 1264-1271, 2009

14 Ke Z, "Sonic hedgehog-Gli1 signals promote epithelial-mesenchymal transition in ovarian cancer by mediating PI3K/AKT pathway" 32 : 368-, 2015

15 Islam SS, "Sonic hedgehog(Shh)signaling promotes tumorigenicity and stemness via activation of epithelial-to-mesenchymal transition(EMT)in bladder cancer" 55 : 537-551, 2015

16 Gratton JP, "Selective inhibition of tumor microvascular permeability by cavtratin blocks tumor progression in mice" 4 : 31-39, 2003

17 Maharjan S, "Sac-0601prevents retinal vascular leakage in a mouse model of diabetic retinopathy" 657 : 35-40, 2011

18 Shahi MH, "Regulation of sonic hedgehog-GLI1 downstream target genes PTCH1, Cyclin D2, Plakoglobin, PAX6 and NKX2.2 and their epigenetic status in medulloblastoma and astrocytoma" 10 : 614-, 2010

19 Li X, "Paracrine sonic hedgehog signaling derived from tumor epithelial cells : a key regulator in the pancreatic tumor microenvironment" 22 : 97-108, 2012

20 Steinway SN, "Network modeling of TGFbeta signaling in hepatocellular carcinoma epithelial-to-mesenchymal transition reveals joint sonic hedgehog and Wnt pathway activation" 74 : 5963-5977, 2014

21 Wang XD, "Mutations in the hedgehog pathway genes SMO and PTCH1 in human gastric tumors" 8 : e54415-, 2013

22 Han Y, "Molecular mechanism underlying the tumorpromoting functions of carcinoma-associated fibroblasts" 36 : 1385-1394, 2015

23 Winkler F, "Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases" 6 : 553-563, 2004

24 Harris LG, "Increased vascularity and spontaneous metastasis of breast cancer by hedgehog signaling mediated upregulation of cyr61" 31 : 3370-3380, 2012

25 Olsen CL, "Hedgehoginteracting protein is highly expressed in endothelial cells but downregulated during angiogenesis and in several human tumors" 4 : 43-, 2004

26 Geng L, "Hedgehog signaling in the murine melanoma microenvironment" 10 : 259-267, 2007

27 Harris LG, "Hedgehog signaling : networking to nurture a promalignant tumor microenvironment" 9 : 1165-1174, 2011

28 Ohlund D, "Fibroblast heterogeneity in the cancer wound" 211 : 1503-1523, 2014

29 Chuang PT, "Feedback control of mammalian Hedgehog signaling by the Hedgehog-binding protein, Hip1, modulates Fgf signaling during branching morphogenesis of the lung" 17 : 342-347, 2003

30 Tada M, "Downregulation of hedgehog-interacting protein through genetic and epigenetic alterations in human hepatocellular carcinoma" 14 : 3768-3776, 2008

31 Chen W, "Canonical hedgehog signaling augments tumor angiogenesis by induction of VEGF-A in stromal perivascular cells" 108 : 9589-9594, 2011

32 Cirri P, "Cancer-associated-fibroblasts and tumour cells : a diabolic liaison driving cancer progression" 31 : 195-208, 2012

33 Augsten M, "Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment" 4 : 62-, 2014

34 Damhofer H, "Assessment of the stromal contribution to Sonic Hedgehog-dependent pancreatic adenocarcinoma" 7 : 1031-1042, 2013

35 Sekulic A, "Advanced basal cell carcinoma of the skin : targeting the hedgehog pathway" 25 : 218-223, 2013

36 Martin ST, "Aberrant methylation of the Human Hedgehog interacting protein(HHIP)gene in pancreatic neoplasms" 4 : 728-733, 2005