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Cathepsins and their inhibitors in head and neck cancer<br />
Primo` Strojan<br />
Department of Radiation Oncology, Institute of Oncology, Zalo{ka 2, SI-1000 Ljubljana,<br />
Slovenia (pstrojan@onko-i.si)<br />
Head and neck cancer comprises approximately 5% of newly diagnosed invasive<br />
malignancies. More than 95 % of tumors are of epithelial origins: histologically<br />
they belong to the group of squamous cell carcinomas. Alcohol and tobacco abuse<br />
are common etiologic factors for oral cavity, oropharyngeal, hypopharyngeal,<br />
and laryngeal cancers. Moreover, because the entire aerodigestive epithelium<br />
may be exposed to these carcinogens, patients with head and neck cancer are at<br />
risk for developing second primary neoplasms of the head and neck, lung, and<br />
esophagus.<br />
Successful treatment of head and neck cancer requires accurate risk stratification to<br />
determine the type and extent of therapy needed and the expected clinical outcome.<br />
Physical examination, diagnostic imaging studies, and pathologic review are aimed<br />
to determine the size and extent of the primary tumor (T-stage), the status of regional<br />
(cervical) lymph nodes (N-stage), and the likelihood of systemic metastases (Mstage).<br />
In addition to TNM staging, other clinical and pathological factors have been<br />
shown to influence response to therapy and outcome.<br />
Cathepsins are a group of lysosomal cysteine (cathepsins B, H, L and others) or<br />
aspartic proteases (cathepsin D) that are involved predominantly in phagolysosomal<br />
protein degradation. Most of the cathepsins are expressed ubiquitously, but a few<br />
demonstrate strict tissue specificity. Endogenous inhibitors of cysteine cathepsins<br />
belong to cystatins, which are subdivided into three families, i.e. stefins, cystatins,<br />
and kininogens, and thyropins, whereas the naturally occurring inhibitor of aspartic<br />
protease, cathepsin D, has not been found yet in men.<br />
l15<br />
29<br />
During the last decades it has been shown that pericellular proteolysis has multiple<br />
roles in virtually all aspects of the normal life of a cell, such as protein degradation,<br />
antigen presentation, bone resorption and hormone processing. The same process<br />
is involved in the degradation of extracellular matrix barriers during invasion and<br />
metastasizing.<br />
The predictive and prognostic value of individual cathepsins and their inhibitors<br />
was widely investigated in breast, lung, and colorectal carcinoma. Compared to<br />
these tumors, the squamous cell carcinoma of the head and neck fall into much less<br />
investigated group of cancers. Apart from the studies focused to the activity or level<br />
of cathepsins and their inhibitors as determined in matched pairs of tumor tissue<br />
and normal mucosa, there are only a limited number of reports in the literature<br />
assessing their predictive or prognostic value in this H&N cancer. There are several<br />
reasons, the two most important being:<br />
• head and neck cancers appear to be a heterogeneous group of tumors<br />
consisting of multiple primary sites inside the upper aerodigestive tract,<br />
each with its own natural history and treatment outcome
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