Pancreatic tumor cell secreted CCN1/Cyr61 promotes endothelial cell migration and aberrant neovascularization.
The complex signaling networks between cancer cells and adjacent endothelial cells make it challenging to unravel how cancer cells send extracellular messages to promote aberrant vascularization or tumor angiogenesis. Here, in vitro and in vivo models show that pancreatic cancer cell generated unique microenvironments can underlie endothelial cell migration and tumor angiogenesis. Mechanistically, we find that pancreatic cancer cell secreted CCN1/Cyr61 matricellular protein rewires the microenvironment to promote endothelial cell migration and tumor angiogenesis. This event can be overcome by Sonic Hedgehog (SHh) antibody treatment. Collectively, these studies identify a novel CCN1 signaling program in pancreatic cancer cells which activates SHh through autocrine-paracrine circuits to promote endothelial cell migration and tumor angiogenesis and suggests that CCN1 signaling of pancreatic cancer cells is vital for the regulation of tumor angiogenesis. Thus CCN1 signaling could be an ideal target for tumor vascular disruption in pancreatic cancer.
1] Cancer Research Unit, Kansas City VA Medical Center, Kansas City, MO [2] Division of Hematology and Oncology, University of Kansas Medical Center, Kansas City, Kansas [3].
Gargi
G
Maity
1] Cancer Research Unit, Kansas City VA Medical Center, Kansas City, MO [2].
Smita
S
Mehta
1] Cancer Research Unit, Kansas City VA Medical Center, Kansas City, MO [2] Division of Hematology and Oncology, University of Kansas Medical Center, Kansas City, Kansas.
Inamul
I
Haque
1] Cancer Research Unit, Kansas City VA Medical Center, Kansas City, MO [2].
Kakali
K
Dhar
1] Cancer Research Unit, Kansas City VA Medical Center, Kansas City, MO [2] Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas.
Sandipto
S
Sarkar
1] Cancer Research Unit, Kansas City VA Medical Center, Kansas City, MO [2] Division of Hematology and Oncology, University of Kansas Medical Center, Kansas City, Kansas [3] Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas [4] Department of Pathology, University of Kansas Medical Center, Kansas City, Kansas.
Sushanta K
SK
Banerjee
1] Cancer Research Unit, Kansas City VA Medical Center, Kansas City, MO [2] Division of Hematology and Oncology, University of Kansas Medical Center, Kansas City, Kansas.
Snigdha
S
Banerjee
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D055515:Cysteine-Rich Protein 61 / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D059016:Tumor Microenvironment / Q000502:physiology
D055515:Cysteine-Rich Protein 61; D053823:Hedgehog Proteins