Cathepsin protease expression in infiltrative soft tissue sarcomas: Cathepsin-K correlates with infiltrative tumor growth and clinical outcomes Journal Article


Authors: Fujiwara, T.; Zhang, L.; Chandler, A.; Sung, S.; Yakoub, M.; Linkov, I.; Hameed, M.; Healey, J. H.
Article Title: Cathepsin protease expression in infiltrative soft tissue sarcomas: Cathepsin-K correlates with infiltrative tumor growth and clinical outcomes
Abstract: Cathepsin proteases, activated in the lysosomes, are upregulated in many cancers. Intraoperative detection systems of microscopic residual tumor using cathepsin-mediated release of fluorescent nanoparticles may guide surgical excisions to improve local control. We sought to define the genetic and proteomic expression of cathepsins and their clinicopathological correlates in myxofibrosarcoma and undifferentiated pleomorphic sarcoma (UPS)—soft tissue sarcomas with high rates of positive resection margins and local recurrence—and to establish a cellular justification for cathepsin-dependent systems to identify residual cancer in the resection bed. Real-time quantitative polymerase chain reaction analysis of 58 fresh-frozen tumor specimens revealed that 56 (97%) had elevated mRNA expression of ≥1 cathepsin, including cathepsin-B (79%), cathepsin-K (59%), cathepsin-L (71%), and -S (71%). Immunohistochemical analysis of these fresh-frozen specimens revealed that 98% of tumors were positive for one or more of cathepsin-B (85%), cathepsin-K (50%), cathepsin-L (63%), and -S (10%). Strong cathepsin-K expression was associated with greater risks of local recurrence (hazard ratio, 3.78; p = 0.044) and disease-specific mortality (hazard ratio, 3.70; p = 0.025). Immunohistochemical analysis of 33 formalin-fixed paraffin-embedded block samples revealed that 97% were positive for cathepsin-B (88%), cathepsin-K (76%), cathepsin-L (52%), or -S (52%) at the tumor periphery; cathepsin-K positivity correlated with a radiographic tail-like sign (p = 0.004) and microscopic infiltrative growth (p = 0.020). We conclude that cathepsins are broadly overexpressed in myxofibrosarcoma and UPS, and cathepsin-K may be an immunohistochemical marker of local infiltration and poorer prognosis that could be used to guide precision surgery. © 2022
Keywords: adult; genetics; metabolism; pathology; proteomics; sarcoma; fibrosarcoma; soft tissue sarcoma; cathepsin; cathepsins; malignant fibrous histiocytoma; soft tissue neoplasms; soft tissue tumor; peptide hydrolases; peptide hydrolase; histiocytoma, malignant fibrous; myxofibrosarcoma; undifferentiated pleomorphic sarcoma; humans; prognosis; human; infiltrative behavior
Journal Title: Human Pathology
Volume: 134
ISSN: 0046-8177
Publisher: Elsevier Inc.  
Date Published: 2023-04-01
Start Page: 30
End Page: 44
Language: English
DOI: 10.1016/j.humpath.2022.12.006
PUBMED: 36565726
PROVIDER: scopus
PMCID: PMC10748737
DOI/URL:
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: John H. Healey -- Source: Scopus
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MSK Authors
  1. Meera Hameed
    286 Hameed
  2. John H Healey
    551 Healey
  3. Irina Linkov
    75 Linkov
  4. Lingxin Zhang
    8 Zhang
  5. Mohamed Ahmed Ali Yakoub
    18 Yakoub
  6. Shijun Sung
    1 Sung