Abstract
Inflammation in the tumor bed can either promote or inhibit tumor growth. Peroxisome proliferator-activated receptor (PPAR)α is a central transcriptional suppressor of inflammation, and may therefore modulate tumor growth. Here we show that PPARα deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of the endogenous angiogenesis inhibitor thrombospondin-1 and prevents tumor growth. Bone marrow transplantation and granulocyte depletion show that PPARα expressing granulocytes are necessary for tumor growth. Neutralization of thrombospondin-1 restores tumor growth in PPARα-deficient mice. These findings suggest that the absence of PPARα activity renders inflammatory infiltrates tumor suppressive and, thus, may provide a target for inhibiting tumor growth by modulating stromal processes, such as angiogenesis.
Highlights
Non-neoplastic ‘‘host’’ cells, such as endothelial, stromal and inflammatory cells, play a critical role in tumor growth; and genes prognostic for cancer outcome may be expressed in the nonneoplastic tissue compartment [1]
Given that the above results clearly suggest that the status of the PPARa locus in the host affects tumor growth, we evaluated the growth of three PPARa-positive murine tumor models in PPARa KO (S4) animals, including Lewis lung carcinoma (LLC), metastatic B16-F10/GFP melanoma, and B16-BL6 melanoma, p,0.001 (Figure 1E–G)
When re-transplanted to PPARa WT mice, these tumors grew rapidly to over 10,000 mm3 (Figure 2A) indicating that PPARa in the host can rescue PPARa 2/2 tumor cells. These findings suggest that the presence of PPARa both in the tumor cells as well as in the host is necessary for unabated tumor growth, they demonstrate that PPARa in tumor cells is not necessary for tumor cell viability
Summary
Non-neoplastic ‘‘host’’ cells, such as endothelial, stromal and inflammatory cells, play a critical role in tumor growth; and genes prognostic for cancer outcome may be expressed in the nonneoplastic tissue compartment [1]. While tumor angiogenesis has been intensely studied for more than two decades and has become an accepted target in cancer therapy, it is only in the last few years that inflammation has entered center stage of investigations into non-cell autonomous processes in cancer. Increased infiltration of innate immune cells to the tumor, such as macrophages, mast cells and neutrophils, correlates with increased angiogenesis and poor prognosis [2,3]. NF-kB promotes tumor growth in a cancer cell-autonomous manner by transactivating anti-apoptotic genes, but it stimulates inflammatory processes in the microenvironment that lead to the production of tumor-promoting cytokines [6]
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