Preventing Breast Cancer Metastasis: A Role For Cathepsin C Inhibitors

Breast cancer deaths are often the result of metastasis to distant organs including the lungs.

Overcoming inhibitory mechanisms and establishing growth in new microenvironments is critical to the metastatic process. Using anti-mouse IL-1b (clone B122) and anti-mouse IL-6 (clone MP5-20F3) antibodies from Bio X Cell as one of the research tools, researchers have described a role for the tumour-secreted protease, cathepsin C (CTSC) in helping breast cancer cells use neutrophils to colonize the lungs.

Proteins secreted from breast cancer cell lines with varying metastatic potential

The researchers, led by Dr. Guohong Hu at the Shanghai Institute of Nutrition and Health, began their investigation by looking at proteins secreted from breast cancer cell lines with varying metastatic potential. They observed that:

• • Cell lines with the ability to metastasize to the lung secrete cathepsin C (CTSC), a cysteine protease best known for its function in the lysosomes of immune cells.
  • Lung metastases express more CTSC than primary breast tumours from the same patient.
    • Overexpression of CTSC resulted in more lung metastasis in mouse models.
    • Knockdown of CTSC resulted in decreased lung colonization and longer metastasis-free survival.
    • Overexpression and knockdown experiments also revealed that CTSC promotes the proliferation of cancer cells early in metastasis at the seeding stage.

The researchers, led by Dr. Guohong Hu at the Shanghai Institute of Nutrition and Health, began their investigation by looking at proteins secreted from breast cancer cell lines with varying metastatic potential. They observed that:

• • Cell lines with the ability to metastasize to the lung secrete cathepsin C (CTSC), a cysteine protease best known for its function in the lysosomes of immune cells.
  • Lung metastases express more CTSC than primary breast tumours from the same patient.
    • Overexpression of CTSC resulted in more lung metastasis in mouse models.
    • Knockdown of CTSC resulted in decreased lung colonization and longer metastasis-free survival.
    • Overexpression and knockdown experiments also revealed that CTSC promotes the proliferation of cancer cells early in metastasis at the seeding stage.

How cathepsin C regulates lung metastasis

The research team next turned their attention to understanding how CTSC regulates lung metastasis. They found that:

• • Neutrophil infiltration at the early stages of metastasis and demonstrated that tumour seeding is dependent on the presence of these neutrophils.
  • CTSC also promotes the formation of neutrophil extracellular traps (NETs).
    • NETs are comprised of a chromatin scaffold and proteins, including proteases and antimicrobial peptides.
    • These web-like structures function to trap and destroy pathogens but have also been shown to play a role in promoting metastasis.
  • The researchers showed that CTSC activates proteinase 3, a protein-bound to neutrophils.

Using Bio X Cell’s in-vivo antibodies in breast cancer research

Utilizing Bio X Cell’s anti-IL-1b and anti-IL-6 antibodies, researchers demonstrated that:

• • Proteinase 3 activation results in increased IL-1b secretion, nuclear factor-kB activation, and release of IL-6 as well as C-C motif chemokine ligand 3.
    • They serve as chemoattractants to recruit neutrophils to newly established lung metastases
  • Inhibiting the process of CTCS-induced NET formation could foil breast cancer cells and prevent them from establishing lung metastases.
  • Mice treated with a CTCS inhibitor (AZD7986) formed fewer NETs and had fewer lung metastases and improved survival.
  • These findings set the stage for future research and potential treatments to prevent deadly lung metastasis in breast cancer.

Read the full article in Cancer Cell here.

Reference:

1. Preventing Breast Cancer Metastasis: A Role for Cathepsin C Inhibitors. BioXCell, 12 Oct. 2021, https://blog.bxcell.com/preventing-breast-cancer-metastasis-a-role-for-cathepsin-c-inhibitors.