Human Gastrointestinal Neoplasia-Associated Myofibroblasts Can Develop from Bone Marrow-Derived Cells Following Allogeneic Stem Cell Transplantation

Abstract

This study characterized the contribution of bone marrow-derived cells to human neoplasia and the perineoplastic stroma. The Australasian Bone Marrow Transplant Recipient Registry was used to identify solid organ neoplasia that developed in female recipients of male allogeneic stem cell transplants. Eighteen suitable cases were identified including several skin cancers, two gastric cancers, and one rectal adenoma. Light microscopy, fluorescence and chromogenic in situ hybridization, and immunohistochemistry were performed to determine the nature and origin of the neoplastic and stromal cells. In contrast to recent reports, donor-derived neoplastic cells were not detected. Bone marrow-derived neoplasiaassociated myofibroblasts, however, were identified in the rectal adenoma and in a gastric cancer. Bone marrowderived cells can generate myofibroblasts in the setting of human gastrointestinal neoplasia.

Mesenchymal Stem Cells: How Can we Realize their Therapeutic Potential in Cancer Therapy?

“…In vivo, inhibitors of stromal-cell derived factor-1α blocked MSC recruitment and tumour development in a mouse model of gastric cancer [13].…”

“…Mouse model studies have concluded that anywhere between 20% and 90% of tumour associated fibroblasts are derived from MSCs [2,3,[10][11][12], which may highlight tumour model-specific differences as well as varying definitions of the MSC. In a rare human-based study, activated fibroblasts with Y chromosomes were found in female allogenic bone marrow transplant patients with rectal and gastric neoplasia, who had earlier received bone marrow from male donors [13].…”

“…MSCs were shown to increase initiation and growth rates of a variety of tumour types including gastric cancer [13], esophageal cancer [14] and MCF7/Ras breast cancer [4], generally through the secretion of anti-apoptotic and pro-proliferative cytokines, for example via production of CCL5 (RANTES) and interleukin-6 in breast cancer models ( [4,15] and see Zimmerlin et al [16] for a more complete list of cytokines). It is also possible that cytokines found to be produced by MSCs in non-cancerous situations, for example, in wound healing, hematopoiesis and arteriogenesis, might also be secreted in cancer [17][18][19].…”

“…Cytokines involved in MSC attraction towards tumours include interleukin-6 and -8, neurotrophin-3, transforming growth factor-β and stromal-cell derived factor-1 α, which were shown to be important in various cancer cell types including glioma, colorectal and breast cancers [13,38,[41][42][43][44]. In vivo, inhibitors of stromal-cell derived factor-1α blocked MSC recruitment and tumour development in a mouse model of gastric cancer [13].…”

“…Studies in pancreatic cancer have found that the proportion of MSCs in a tumour increases as time goes on [65,66], suggesting blocking the MSC homing process towards a tumour might alter the normal tumour progression. In vivo studies examining cytokine effect in MSC recruitment have shown that even a partial block of MSC recruitment can lead to a reduction in tumour size and metastasis [13,39]. In another study, using conditional knockout in a background of transgenic C57Bl/6 mice, Nestin-positive cells were depleted in bone marrow and the effect on the hematopoietic stem cell niche studied.…”