Presentation Highlights

Tumors are dependent on a sustained influx of cytokine-releasing leukocytes, mostly macrophages, for growth. During Thursday’s Platelets and Inflammation Oral Session, Nicolas Prévost, Ph.D. presented findings of his study on the existence of distinct tumor-associated macrophages. This study showed:

  • Tumor-associated macrophages are only found in highly fibrotic regions of tumors
  • These macrophages have the ability to transition from arrest to extravasation following VWF-platelet cluster internalization

These findings are important because they suggest that disruption of VWF-platelet-leukocyte interactions may help to curtail tumor-associated inflammation and fibrosis, thereby decreasing tumor metastases.

In cancers, tumor fibrosis constitutes a risk factor for metastasis. This chronic inflammatory state is accompanied by the release of von Willebrand factor (VWF) from tumor-associated blood vessels. Because platelets are known to mediate the entry of immune cells into inflamed tissues and because VWF has been linked to fibrosis, this study evaluated whether VWF would support the formation of microthrombi and act as homing a signal for fibrosis-causing tumor-associated macrophages (TAMs).

Immunohistological analysis was performed on tumor biopsies from cancer patients to assess the presence of macrophage-platelet-VWF clusters. The existence of a distinct TAM population was revealed; one that presents with strong VWF and platelet integrin αIIb co-staining. Strikingly, those VWF+/αIIb+ TAMs were only found in highly fibrotic regions of the tumor. Complementary in vitro studies were performed to elucidate the molecular mechanisms underlying macrophage binding to VWF-bound platelets; these studies confirmed the importance of VWF-bearing microthrombi for macrophage homing as well as the importance of integrin αMβ2. They also yielded a novel finding: macrophage transition from arrest to extravasation only occurs following internalization of VWF-platelet clusters.

In these investigations, Prévost and colleagues identified a novel mechanism through which macrophages infiltrate tumor territory, one that is dependent on their binding and engulfing of VWF-bearing microthrombi. This TAM sub-population appears to bear strong pro-fibrotic potential. These observations suggest that the disruption of VWF-platelet-macrophage interactions may help to curtail tumor inflammation and fibrosis, and ultimately decrease the metastatic potential of certain tumors.

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