BACKGROUND

Vascular endothelial growth factor (VEGF), a recently identified growth factor with significant angiogenic properties, is a multifunctional angiogenic cytokine that is expressed in many tumors. High VEGF expression has been shown to correlate with the incidence of metastasis and poor prognosis in various cancers. In this study, the authors investigated VEGF expression and microvessel density (MVD) in ductal pancreatic adenocarcinoma and examined the correlations among VEGF expression, clinicopathologic factors, and clinical outcome. The authors especially focused on the correlation between VEGF expression and liver metastasis.



METHODS

Paraffin embedded tumor specimens of 142 surgically resected pancreas carcinoma were immunohistochemically stained for VEGF and MVD. The correlations among VEGF expression and MVD, clinicopathologic factors, and clinical outcome were then statistically analyzed.



RESULTS

One hundred thirty-two (93%) of 142 ductal pancreatic adenocarcinomas were positive for VEGF protein by immunohistochemistry. A significant correlation was observed between VEGF positivity and MVD (P < 0.0001). Multivariate logistic regression analysis indicated a significant association between high VEGF expression and liver metastasis (P = 0.010) but no other factors, such as age, tumor size, histologic type, lymph node metastasis, venous invasion, neural invasion, peritoneal metastasis, or local recurrence. Patients with tumors that showed moderate or high VEGF expression had significantly shorter survival than patients with low VEGF expression or none at all in their tumors (P < 0.05).



CONCLUSIONS

These results indicate that VEGF expression is closely correlated with MVD and seems to be an important predictor for both liver metastasis and poor prognosis in ductal pancreatic adenocarcinoma. Cancer 2000;88:2239–45. © 2000 American Cancer Society.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/%28SICI%291097-0142%2820000515%2988%3A10%3C2239%3A%3AAID-CNCR6%3E3.0.CO%3B2-V

High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma

Purpose : The purpose of the following study was to investigate the safety and efficacy of the novel multitargeted indolinone receptor tyrosine kinase (RTK) inhibitor, SU11654, using a canine model of spontaneous tumors. This p.o. bioavailable compound exhibits potent inhibitory activity against members of the split kinase family of RTKs, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor, Kit, and Flt-3, resulting in both direct antitumor and antiangiogenic activity. Experimental Design : This was a Phase I trial in which successive cohorts of dogs with spontaneous tumors that had failed standard treatment regimens received escalating doses of SU11654 as oral therapy. Pharmacokinetics, toxicity, and tumor response were assessed. Results: Fifty-seven dogs with a variety of cancers were enrolled; of these, 10 experienced progressive disease within the first 3 weeks. Measurable objective responses were observed in 16 dogs (including 6 complete responses), primarily in mast cell tumors ( n = 11), mixed mammary carcinomas ( n = 2), soft tissue sarcomas ( n = 2), and multiple myeloma ( n = 1), for an overall response rate of 28% (16 of 57). Stable disease of sufficient duration to be considered clinically meaningful (>10 weeks) was seen in an additional 15 dogs, for a resultant overall biological activity of 54% (31 of 57). Conclusions : This study provides the first evidence that p.o. administered kinase inhibitors can exhibit activity against a variety of spontaneous malignancies. Given the similarities of canine and human cancers with regard to tumor biology and the presence of analogous RTK dysregulation, it is likely that such agents will demonstrate comparable antineoplastic activity in people.

https://clincancerres.aacrjournals.org/content/clincanres/9/7/2755.full.pdf

Phase I Dose-Escalating Study of SU11654, a Small Molecule Receptor Tyrosine Kinase Inhibitor, in Dogs with Spontaneous Malignancies,

It has been thought that there is a strong relationship between inflammation and carcinogenesis so that the development of cancer occurs with chronic inflammation in many organs. An in-depth understanding of the mechanism by which inflammation can lead to carcinogenesis may enable the development of drugs targeted at important molecules, providing a powerful tool for preventing cancer development. In this review, we focused on a signal transduction system, the nuclear factor-kappaB (NF-kappaB) pathway, which is thought to play a role in the process leading from inflammation to carcinogenesis, and may thus serve as a candidate for targeted intervention.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1349-7006.2008.00763.x

Inflammation and cancer: role of nuclear factor-kappaB activation.

Introduction and AimsOnly curative resection for pancreatic adenocarcinoma is related to a favorable prognosis, but the overall survival after surgery still remains poor, and early recurrence is frequently observed. Because recurrence is the limiting factor and the main cause of death after curative

High expression of vascular endothelial growth factor predicts early recurrence and poor prognosis after curative resection for ductal adenocarcinoma of the pancreas.

Muscle injuries are very common in traumatology and sports medicine Although muscle tissue can regenerate postinjury, the healing process is slow and often incomplete; complete recovery after skel

https://www.physiology.org/doi/pdf/10.1152/japplphysiol.00915.2002

Antifibrotic effects of suramin in injured skeletal muscle after laceration

A wide range of growth factors has been identified in recent years, some of which have been found to play a crucial role in neoplastic processes. Some tumours produce considerable amounts of these peptides and their requirement for growth factors is often much reduced leading to a degree of autonomy which may itself contribute to tumourigenicity. In addition, growth factors such as TGF-alpha, PDGF, FGF and IGFs have been found to be overexpressed in tumours. The growth factor effector pathway is thus open to intervention, e.g. by blocking the receptor using specific antibodies or interfering with posttranscriptional activation. This is even more evident as oncogenes such as erbB and v-sis encode for growth factor receptors. Soluble receptors, due to high affinity binding, might also be used to sequester growth factors from its specific membrane-bound receptors. Tyrosine-specific protein kinase activity may be inhibited by tyrosine analogues such as erbstatin or by more specific tyrosine-kinase inhibitors. Some therapeutical concepts have already been developed in clinical trials. Tumour necrosis factor (TNF) has successfully been used in extremity melanoma and sarcoma and monoclonal antibodies directed against the EGF receptor has also been applied in patients with advanced squamous lung cancer. Synthetic growth factor analogues which bind to the receptor without eliciting a signal may soon become a supplementary part in cancer treatment. Growth factor action is also blocked by suramin and its analogues and clinical phase I and II trials are underway. These novel therapeutical aspects will profoundly change the nature of cancer treatment.

Zumkeller W

Papers

Growth factors, cytokines and soluble forms of receptor molecules in cancer patients.