The role of Osteopontin in tumor metastasis

Tenascin-C induced signaling in cancer.

Vascular endothelial growth factor (VEGF), released by tumor cells, is an important growth factor in tumor angiogenesis. The humanized monoclonal antibody bevacizumab blocks VEGFinduced tumor angiogenesis by binding, thereby neutralizing VEGF. Our aim was to develop radiolabeled bevacizumab for noninvasive in vivo VEGF visualization and quantification with the single g-emitting isotope 111 In and the PET isotope 89 Zr. Methods: Labeling, stability, and binding studies were performed. Nude mice with a human SKOV-3 ovarian tumor xenograft were injected with 89Zr-bevacizumab, 111In-bevacizumab, or human 89 Zr-IgG. Human 89 Zr-IgG served as an aspecific control antibody. Small-animal PET and microCT studies were obtained at 24, 72, and 168 h after injection of 89 Zr-bevacizumab and 89Zr-IgG (3.5 6 0.5 MBq, 100 6 6 mg, 0.2 mL [mean 6 SD]). Small-animal PET and microCT images were fused to calculate tumor uptake and compared with ex vivo biodistribution at 168 h after injection. 89 Zr- and 111 In-bevacizumab ex vivo biodistribution was compared at 24, 72, and 168 h after injection (2.0 6 0.5 MBq each, 100 6 4 mg in total, 0.2 mL). Results: Labeling efficiencies, radiochemical purity, stability, and binding properties were optimal for the radioimmunoconjugates. Small-animal PET showed uptake in well-perfused organs at 24 h and clear tumor localization from 72 h onward. Tumor uptake determined by quantification of small-animal PET images was higher for 89Zr-bevacizumab—namely, 7.38 6 2.06 %ID/g compared with 3.39 6 1.16 %ID/g (percentage injected dose per gram) for human 89Zr-IgG (P 5 0.011) at 168 h and equivalent to ex vivo biodistribution studies. Tracer uptake in other organs was seen primarily in liver and spleen. 89 Zr- and 111 In-bevacizumab biodistribution was comparable. Conclusion: Radiolabeled bevacizumab showed higher uptake compared with radiolabeled human IgG in a human SKOV-3 ovarian tumor xenograft. Noninvasive quantitative small-animal PET was similar to invasive ex vivo biodistribution. Radiolabeled bevacizumab is a new tracer for noninvasive in vivo imaging of VEGF in the tumor microenvironment.

https://jnm.snmjournals.org/content/jnumed/48/8/1313.full.pdf

In Vivo VEGF Imaging with Radiolabeled Bevacizumab in a Human Ovarian Tumor Xenograft

Osteopontin is a secreted phosphoprotein that has been implicated as an important mediator of tumor metastasis and has been investigated for use as a biomarker for advanced disease and as a potential therapeutic target in the regulation of cancer metastasis. The OPN DNA sequence is highly conserved and the protein contains several important functional domains including αvβ integrin and CD44 binding sites. High levels of OPN expression correlate with tumor invasion, progression or metastasis in multiple cancer. Studies demonstrate that osteopontin mediates the molecular mechanisms which determine metastatic spread, such as prevention of apoptosis, extracellular matrix proteolysis and remodeling, cell migration, evasion of host-immune cells and neovascularization. Transcriptional regulation of OPN is complex and involves multiple pathways, including AP-1, Myc, v-Src, Runx/CBF, TGF-B/BMPs/Smad/Hox, and Wnt/s–catenin/APC/GSK–3s/Tcf-4. The current state of knowledge of OPN biology suggests that it is an attractive target for therapeutic modulation of metastatic disease.

Osteopontin: regulation in tumor metastasis

Biomarkers are used as tools in cancer diagnostics and in treatment stratification. In most cancers, there are increased levels of one or several members of the matrix metalloproteinases (MMPs). This is a family of proteolytic enzymes that are involved in many phases of cancer progression, including angiogenesis, invasiveness, and metastasis. It has therefore been expected that MMPs could serve as both diagnostic and prognostic markers in cancer patients, but despite a huge number of studies, it has been difficult to establish MMPs as cancer biomarkers. In the present paper, we assess some of the challenges associated with MMP research as well as putative reasons for the conflicting data on the value of these enzymes as diagnostic and prognostic markers in cancer patients. We also review the prognostic value of a number of MMPs in patients with lung, colorectal, breast, and prostate cancers. The review also discusses MMPs as potential target molecules for therapeutic agents and new strategies for development of such drugs.

Matrix metalloproteinases in cancer: their value as diagnostic and prognostic markers and therapeutic targets

Osteopontin overproduced by tumor cells acts as a potent angiogenic factor contributing to tumor growth.

Although vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9 are involved in angiogenesis of various cancers, clinical utility of preoperative serum concentration of these molecules in non-small cell lung cancer (NSCLC) has not yet been elucidated. In this study, we determined the concentration of VEGF, MMP-9 and various other tumor markers in serum prior to surgery and evaluated the results compared with intratumoral vasculature to isolate a valuable marker in determining the prediction of angiogenesis in NSCLC. Among these molecules and serum tumor markers, circulating serum VEGF was identified to markedly correlate with microvessel density (MVD) of the resected tumor specimens. Moreover, overall survival of patients with low VEGF levels (≤326 ng/ml) was significantly greater than that of patients with high VEGF levels (>326 ng/ml), while patients with low MMP-9 levels (≤189 ng/ml) and those with high MMP-9 levels (>189 ng/ml) revealed similar overall survival. Conclusively, preoperative concentration of serum VEGF may be the most valuable marker in the prediction of intratumoral angiogenesis and prognosis of patients with NSCLC.

Role of Serum Vascular Endothelial Growth Factor in the Prediction of Angiogenesis and Prognosis for Non-small Cell Lung Cancer

Background: Tenascin (Tn)-C is an extracellular matrix protein that is involved in tissue interactions during fetal development and oncogenesis. However, the role of serum Tn- C in non-small cell lung cancer (NSCLC) has not been clarified. Patients and Methods: In this study, we determined the serum levels of Tn-C among NSCLC patients who underwent surgery, as well as other factors implicated for angiogenesis, to address the clinical implications in NSCLC. Results and Conclusion: The median concentration of serum Tn-C in NSCLC patients was slightly higher than that of normal controls, but this difference was not statistically significant. There was a positive correlation between serum Tn- C levels and microvessel density (MVD), serum osteopontin (OPN) and vascular endothelial growth factor (VEGF). In contrast, there was no correlation between serum Tn-C levels and serum carcinoembryonic antigen (CEA) and sialyl lewis-X (SLX) levels. The overall survival of patients with low Tn-C levels (<96 ng/ml) was significantly greater than that of patients with high Tn-C levels (≥96 ng/ml). Intratumoral Tn- C expression was co-localized with expression of microvessels in the stroma of the cancer cells by immunohistochemical analysis. Moreover, enhanced in vitro migration of human umbilical vascular endothelial cells (HUVEC) was induced by recombinant Tn-C. Collectively, Tn-C may play an important role in angiogenesis of patients with NSCLC, and the determination of serum Tn-C may be useful in predicting intratumoral vasculature and patients' prognosis.

Serum tenascin-C as a potential predictive marker of angiogenesis in non-small cell lung cancer.

A 38-year-old woman was admitted due to lymphangioleiomyomatosis (LAM)-associated massive chylous ascites and progressive cachexia. She was incidentally diagnosed to have ascites during her regular physical check-up two years previously and LAM was revealed as its underlying cause. Periodic paracentesis was required to ameliorate ascites-associated symptoms, but resulted in lymphocytopenia, malnutrition, and deterioration of general status. Ascites was refractory to diuretics and fat-restricted diet. Peritoneovenous shunt (Denver shunt®) was placed and thereafter ascites has been managed successfully without any complications for one year after the placement. Peritoneovenous shunt should be considered in LAM patients whose chylous ascites can not be managed with conservative treatments.

Peritoneovenous Shunting for Intractable Chylous Ascites Complicated with Lymphangioleiomyomatosis

An asymptomatic patient with exogenous lipoid pneumonia (ELP) due to silent aspiration of liquid paraffin ingested as a lubricant was diagnosed by bronchoalveolar lavage (BAL). BAL fluid separated into oily upper phase and lower aqueous phase spontaneously. Microscopic analysis of BAL cells revealed the presence of lipid-laden alveolar macrophages. Classic histochemical staining and electron microscope examination indicated that neutral lipid was dominant but phospholipid was also present in the lipid-laden macrophages. Together with the history of ingestion of liquid paraffin, we identified that the ingested liquid paraffin was the origin of the neutral lipid in the lipid-laden macrophages observed in the BAL fluid.

Yuri Shimanuki

Papers

Osteopontin overproduced by tumor cells acts as a potent angiogenic factor contributing to tumor growth.

Role of Serum Vascular Endothelial Growth Factor in the Prediction of Angiogenesis and Prognosis for Non-small Cell Lung Cancer

Serum tenascin-C as a potential predictive marker of angiogenesis in non-small cell lung cancer.

Peritoneovenous Shunting for Intractable Chylous Ascites Complicated with Lymphangioleiomyomatosis

Exogenous Lipoid Pneumonia Following Ingestion of Liquid Paraffin