Structured myeloid cells and anti-angiogenic therapy in alveolar soft part sarcoma

Abstract

Alveolar soft part sarcoma (ASPS) is a rare soft tissue sarcoma and the clinical management of patients with unresectable, metastatic disease is still challenging. ASPS expresses an array of potentially therapeutically targetable, angiogenesis-related molecules and, importantly, it has a distinctive angiogenic phenotype marked by a peculiar tumor-associated vasculature. Several studies, conducted in transgenic mouse models and in a large variety of human tumors of different histotype, clearly proved the substantial contribution of tumor-infiltrating myeloid cells, such as myeloid derived suppressor cells, monocytes and macrophages, in the formation and maintenance of abnormal blood vessels in tumors. By immunohistochemistry we thus explored the presence and the distribution of cells expressing myeloid markers in the inflammatory infiltrate of surgical treated metastatic ASPS. Indeed, we found that myeloid cells expressing CD14 and CD163 markers constitute the prominent cells in the inflammatory infiltrate of ASPS. These macrophage-like cells form a network surrounding the endothelial cells, or, interspersed in the tumor nest, they keep deep contact with tumor cells. In this commentary, we discussed our findings in relation to the recently published paper by Kummar and colleagues reporting the clinical and molecular results of a phase II clinical trial in patients with unresectable, metastatic ASPS treated with the anti-angiogenic drug cediranib, targeting the VEGFR-1,-2,-3 tyrosine kinases.

Figure 1

Macrophages are key components of the inflammatory microenvironment in metastatic alveolar soft part sarcoma. Immunohistochemical analysis of CD163+ cells infiltrating an untreated ASPS lesion (A-B). As evidenced by the higher magnification image these cells are found in two distinct localizations: they are interspersed within nest tumor cells (circle) and they are also detectable in the perivascular region (arrows). (B) Confocal microscopy imaging of CD163+ cells (green) shows that they are aligned to endothelial VEGFR2+ cells (red) (C). CD14 staining closely resembles that of CD163 (D) and double staining confirms that CD31+ endothelial cells (green) are lined by CD14+ macrophages (red). (E) A similar distribution of immunoreactivity is observed for CSFR-1 (F).