Dynamic interactions between tumorigenic cells and surrounding cells, including immunomodulatory hematopoietic cells, can dictate
tumor initiation, progression, and transformation. Hematopoietic-stromal interactions underpin the
plexiform neurofibroma, a debilitating
tumor arising in individuals afflicted with
Neurofibromatosis type 1 (NF1), a common
genetic disorder resulting from mutations in the NF1 tumor suppressor gene. At the tissue level,
plexiform neurofibromas demonstrate a complex microenvironment composed of Schwann cells, fibroblasts, perineural cells, mast cells, secreted
collagen, and blood vessels. At the cellular level, specific interactions between these cells engender
tumor initiation and progression. In this microenvironment hypothesis, tumorigenic Schwann cells secrete pathological concentrations of
stem cell factor, which recruit c-kit expressing mast cells. In turn, activated mast cells release inflammatory effectors stimulating the tumorigenic Schwann cells and their supporting fibroblasts and blood vessels, thus promoting
tumor expansion in a feed-forward loop.
Bone marrow transplantation experiments in
plexiform neurofibroma mouse models have shown that
tumorigenesis requires Nf1 haploinsufficiency in the hematopoietic compartment, suggesting that tumor microenvironments can depend on intricate interactions at both cellular and genetic levels. Overall, our continued understanding of critical
tumor-stromal interactions will illuminate novel therapeutic targets, as shown by the first-ever successful medical treatment of a
plexiform neurofibroma by targeted inhibition of the
stem cell factor/c-kit axis.