Doctoral dissertation
The impact of stefin b and cystatin c deficiency on cancer progression and tumor microenvironment in a mouse breast cancer model
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Abstract
Lysosomal cysteine cathepsins participate in numerous physiological processes and are also involved in pathological conditions such as cancer and inflammation. Proteolytic activity of cysteine cathepsins is tightly regulated by endogenous inhibitors of the cystatin superfamily, among which stefin B is an intracellular, and cystatin C is an extracellular inhibitor. Altered expression of stefin B and cystatin C has been reported in multiple types of cancer; however, their combined roles in tumor progression remain unclear.
In this study, we investigated the role of stefin B (StfB) and cystatin C (CstC) in mammary tumor progression and metastasis. We established a double knockout (DKO) mouse mammary cancer model by crossing StfB and CstC-deficient mice with transgenic polyoma virus middle T oncogene (PyMT) mice that spontaneously develop mammary gland adenocarcinomas. We show that ablation of both StfB and CstC resulted in delayed tumor onset and reduced tumor growth compared to wild-type mice. Furthermore, we detected decreased proliferation and increased apoptosis in DKO tumors, along with significantly reduced pulmonary metastasis in DKO mice. These findings suggest that both inhibitors promote not only primary tumor growth but also metastatic spread.
We next investigated the impact of stefin B and cystatin C deficiency on the tumor microenvironment and immune modulation. Immunohistochemical analysis revealed increased macrophage infiltration in DKO tumors, together with a pronounced shift toward M1 polarization, while M2 populations remained unchanged. This reprogramming of the tumor microenvironment toward an anti-tumor state suggests that stefin B and cystatin C modulate immune responses to favor tumor progression.
Our findings demonstrate that stefin B and cystatin C deficiency affects tumor progression by reducing tumor burden and metastatic spread. Additionally, we showed that stefin B and cystatin C function through complementary mechanisms affecting both tumor cell-intrinsic pathways and the immune landscape.