Altered tumor vessel maturation and proliferation in placenta growth factor‐producing tumors: Potential relationship to post‐therapy tumor angiogenesis and recurrence

Abstract

Cells in human tumor xenografts express similar levels of angiogenic growth factors before treatment. After radioimmunotherapy (RAIT) surviving tumor cells upregulate angiogenic growth factors, including placenta growth factor (PlGF), in a tumor‐specific pattern. To determine the role of post‐treatment PlGF expression on blood vessel recovery, tumor xenografts were assayed for post‐RAIT vessel density (CD34+), proliferation (PCNA+) and maturity (SMA+ pericytes/mural cells). To further analyze the role of PlGF in blood vessel formation, PlGF‐containing Matrigel implants were also assessed in a similar manner. The xenografts producing post‐treatment PlGF increased CD34+ microvessel density 2‐ to 4‐fold over untreated controls (p < 0.05) within 3 weeks of RAIT treatment. The proportion of mature microvessels (SMA+) decreased. Pericyte coverage and density of microvessels remained stable in the tumor that expressed neither PlGF nor VEGF after treatment. Hemoglobin content of PlGF‐containing Matrigel implants was 5.7‐fold that of anti‐PlGF/anti‐VEGF treated controls (Day 6, p < 0.03). The vessel density in PlGF‐implants averaged 36.8 ± 10.6/mm compared to 4.9 ± 6.5/mm² in controls (p < 0.001). Vessels of PlGF‐implants were lined by vWF+ cells, which were mostly flt‐1+. These findings point to a role for PlGF in rapid restoration of tumor blood supply after treatment and thus, to enhanced likelihood of tumor regrowth. Likewise, the cells of primary human tumors that upregulate PlGF after treatment may be more likely to survive and form recurring tumors. Prevention of this angiogenic response to treatment may require administration of anti‐angiogenic therapy during, rather than after, treatment.