Mutations in Bone Marrow-Derived Stromal Stem Cells Unmask Latent Malignancy

Abstract

Neoplastic epithelia may remain dormant and clinically unapparent in human patients for decades. Multiple risk factors including mutations in tumor cells or the stromal cells may affect the switch from dormancy to malignancy. Gene mutations, including p53 mutations, within the stroma of tumors are associated with a worse clinical prognosis; however, it is not known if these stromal mutations can promote tumors in genetically at-risk tissue. To address this question, ApcMin/+ and Apc Min/+ Rag2 −/− mice, which have a predilection to mammary carcinoma (as well as wild-type (wt) mice), received mesenchymal stem cells (MSC) with mutant p53 (p53MSC) transferred via tail vein injection. In the wt mouse, p53MSC circulated in the periphery and homed to the marrow cavity where they could be recovered up to a year later without apparent effect on the health of the mouse. No mammary tumors were found. However, in mice carrying the Apc Min/+ mutation, p53MSC homed to mammary tissue and signifi cantly increased the incidence of mammary carcinoma. Tumor necrosis factor (TNF)-α-dependent factors elaborated from mesenchymal cells converted quiescent epithelia into clinically apparent disease. The increased cancer phenotype was completely preventable with neutralization of TNF-α or by transfer of CD4+ regulatory T cells from immune competent donors, demonstrating that immune competency to regulate infl ammation was suffi cient to maintain neoplastic dormancy even in the presence of oncogenic epithelial and stromal mutations. The signifi cant synergy between host immunity and mesenchymal cells identifi ed here may restructure treatments to restore an anticancer microenvironment.

Inflamm‐aging of the stem cell niche: Breast cancer as a paradigmatic example

“…Although controversial [68], such mutations have been reported in cancer-associated stromal cells, and have been proposed as responsible for the shift toward a cancer-permissive stromal environment [69]. Stromal cells carrying TP53 lossof-function enhance mammary tumor development in cancerprone mice, and promote the growth of breast cancer xenotransplants to a higher extent than in non-mutated counterparts [70,71]. Interestingly, fibroblasts showing a down-regulation of a tumor suppressor (e.g.…”

Malignant transformation of host stromal fibroblasts derived from the bone marrow traced in a dual-color fluorescence xenograft tumor model

“…However, genetic alteration of tumor stromal cells (CAFs) under the influence of the TME, which is known to cause tumor development and progression, has not received much attention. Although several studies have demonstrated the association of certain CAF mutations with carcinomas (21-23), these mutations were only associated with the initiation of epithelial cell carcinomas (19,24) and their role in their own malignant transformation remains to be elucidated. Stromal cells recruited to the TME are termed 'non-tumor' cells and are known to play a role in tumor progression or suppression.…”

Opposing Roles for IL-23 and IL-12 in Maintaining Occult Cancer in an Equilibrium State

“…Mice deficient in tumor necrosis factor alpha (TNF) and IFNAR1 have been demonstrated to have an elevated incidence of MCA-induced sarcomas (21) (22), indicating that these two cytokines are critical players in cancer immunosurveillance. However, the role of TNF in tumor dormancy remains controversial due to contradictory findings in studies of tumor dormancy (23, 24). Here, equilibrium was not altered in different cohorts of MCA treated mice given neutralizing/blocking mAbs to either TNFα or the type I IFN receptor (Fig.…”