Rationale: The progression of
cancer cells depends on the soil and building an inhibitory soil might be a therapeutic option. We previously created
tumor-suppressive secretomes by activating Wnt signaling in MSCs. Here, we examined whether the anti-
tumor secretomes can be produced from
tumor cells. Methods: Wnt signaling was activated in
tumor cells by overexpressing β-
catenin or administering BML284, a Wnt activator. Their
conditioned medium (CM) was applied to
cancer cells or tissues, and the effects of CM were evaluated.
Tumor growth in the mammary fat pad and tibia in C57BL/6 female mice was also evaluated through μCT imaging and histology. Whole-genome proteomics analysis was conducted to determine and characterize novel
tumor-suppressing
proteins, which were enriched in CM. Results: The overexpression of β-
catenin or the administration of BML284 generated
tumor-suppressive secretomes from breast, prostate and
pancreatic cancer cells. In the mouse model, β-
catenin-overexpressing CM reduced
tumor growth and
tumor-driven bone destruction. This inhibition was also observed with BML284-treated CM. Besides p53 and Trail, proteomics analysis revealed that CM was enriched with
enolase 1 (Eno1) and
ubiquitin C (Ubc) that presented notable
tumor-suppressing actions. Importantly, Eno1 immunoprecipitated CD44, a cell-surface
adhesion receptor, and its silencing suppressed Eno1-driven
tumor inhibition. A pan-
cancer survival analysis revealed that the downregulation of MMP9, Runx2 and Snail by CM had a significant impact on survival outcomes (p < 0.00001). CM presented a selective inhibition of
tumor cells compared to non-
tumor cells, and it downregulated PD-L1, an immune escape modulator. Conclusions: The
tumor-suppressive secretome can be generated from
tumor cells, in which β-
catenin presented two opposing roles, as an intracellular
tumor promoter in
tumor cells and a generator of extracellular
tumor suppressor in CM. Eno1 was enriched in CM and its interaction with CD44 was involved in Eno1's anti-
tumor action. Besides presenting a potential option for treating primary
cancers and
metastases, the result indicates that aggressive
tumors may inhibit the growth of less aggressive
tumors via
tumor-suppressive secretomes.