Pancreas Microenvironment Promotes VEGF Expression and Tumor Growth: Novel Window Models for Pancreatic Tumor Angiogenesis and Microcirculation

Abstract

SUMMARY:Pancreatic cancer has a poor prognosis, and treatment strategies based on preclinical research have not succeeded in significantly extending patient survival. This failure likely stems from the general lack of information on pancreatic tumor physiology, attributable to the difficulties in developing relevant, orthotopic models that accurately reflect pancreatic cancer in the clinic. To overcome this limitation, we developed abdominal wall windows suitable for intravital microscopy that allowed us to monitor angiogenesis and microvascular function noninvasively during tumor growth in vivo. We used two complementary tumor models in mice: orthotopic (human ductal pancreatic adenocarcinoma, PANC-1, grown in the pancreas), and ectopic (PANC-1 grown in the abdominal wall). We found that orthotopic PANC-1 tumors grew faster than the ectopic tumors and exhibited metastatic spread in the late stage similar to advanced pancreatic cancer in the clinic. Orthotopic PANC-1 tumors expressed vascular endothelial growth factor (VEGF) 121 and VEGF 165 , contained higher levels of tumor cell-derived VEGF protein, and maintained vascular density and hyperpermeability during exponential tumor growth. Orthotopic PANC-1 tumors showed lower leukocyte-endothelial interactions in the early stage of growth. In addition, both VEGF 121 and VEGF 165 promoted the growth of PANC-1 cells in vitro. Finally, Anti-VEGF neutralizing antibody inhibited angiogenesis and tumor growth of PANC-1 tumors in both sites. We conclude that the orthotopic pancreas microenvironment enhances VEGF expression, which stimulates growth of PANC-1 tumors (compared with ectopic tumors). The mechanism is autocrine and/or paracrine and also is involved in the maintenance of blood vessels. This comparative system of orthotopic and ectopic pancreatic cancer will provide the rigorous understanding of pancreatic tumor pathophysiology needed for development of novel therapeutic strategies. (Lab Invest 2001,

The use of the orthotopic model to validate antivascular therapies for cancer

“…Likewise, the decrease in fenestration pattern and permeability in glioblastoma tumours growing in the brain, compared with those growing subcutaneously, was accompanied by an elevated expression of the receptors for VEGF, whereas expression of VEGF itself did not differ per tumour location (Roberts, 1998). Human ductal pancreatic adenocarcinoma grown in the pancreas of nude mice exhibited enhanced expression of VEGF with concomitant higher growth rate compared with subcutaneous tumours implanted in the abdominal wall (Tsuzuki, 2001). Colon cancer xenografts in their orthotopic location produced higher levels of interleukin-8, carcinoembryonic antigen, as well as multidrug resistance proteins, than their subcutaneously growing counterparts (Kitadai, 1995).…”

Inhibition of constitutive NF-κB activity by IκBαM suppresses tumorigenesis

“…Currently, chemotherapy, radiation therapy, and surgery are largely ineffective in treating this disease (Breslin et al, 2001). Recent studies suggest that VEGF is the best-validated target for antiangiogenic therapies to inhibit angiogenesis and tumor growth in pancreatic cancer (Grisham et al, 1999;Schwarte-Waldhoff et al, 2000;Tsuzuki et al, 2001). Our findings provide important implications for the therapeutic usefulness of NF-kB inhibition in antiangiogenic therapeutic strategies.…”

Kigamicin D, a novel anticancer agent based on a new anti‐austerity strategy targeting cancer cells' tolerance to nutrient starvation

“…7) The well-known observation that hypovascularity is an outstanding characteristic of pancreatic cancers in diagnostic images suggests that pancreatic cancer tissue has a poor blood supply. 8) However, since pancreatic cancers are known to be among the most aggressive malignancies despite their poor blood supply, we proposed that cancer cells' tolerance of insufficient nutrient might be an important determinant of malignancy. 9) Although the mechanism of tolerance has not yet been fully elucidated, the PI-3K-Akt pathway and AMPK have been found to be involved.…”