Mutations in bone marrow-derived stromal stem cells unmask latent malignancy

Area of Science:

• Oncology
• Immunology
• Cancer Biology

Background:

• Neoplastic epithelia can remain dormant for decades.
• Stromal mutations, including p53, are linked to poor prognosis but their role in promoting tumors in at-risk tissue is unclear.
• Mesenchymal stem cells (MSCs) and their mutations may influence tumor development.

Purpose of the Study:

• To investigate if stromal p53 mutations in mesenchymal stem cells (p53MSC) can promote mammary carcinoma in genetically at-risk mice.
• To explore the role of tumor necrosis factor-alpha (TNF-alpha) and immune competency in regulating neoplastic dormancy.
• To identify potential therapeutic strategies for restoring an anticancer microenvironment.

Main Methods:

• Apc(Min/+) and wild-type (wt) mice received p53MSC via tail vein injection.
• Mice were monitored for mammary tumor development.
• Intervention with TNF-alpha neutralization or CD4(+) regulatory T cells was performed.
• Homing patterns of p53MSC were tracked.

Main Results:

• In wt mice, p53MSC did not induce tumors and homed to bone marrow.
• In Apc(Min/+) mice, p53MSC homed to mammary tissue, significantly increasing mammary carcinoma incidence.
• TNF-alpha-dependent factors from mesenchymal cells converted quiescent epithelia to malignancy.
• Tumor incidence was preventable with TNF-alpha neutralization or regulatory T cell transfer.

Conclusions:

• Stromal p53 mutations can promote mammary carcinoma in genetically susceptible hosts.
• Host immune competency, particularly TNF-alpha regulation and regulatory T cells, is critical for maintaining neoplastic dormancy.
• Targeting the interplay between host immunity and mesenchymal cells may offer novel cancer treatment strategies.