Integrins are key regulators of communication between cells and with their microenvironment. Eight members of the integrin superfamily recognize the tripeptide motif Arg-Gly-Asp (RGD) within extracelluar matrix (ECM) proteins. These integrins constitute an important subfamily and play a major role in cancer progression and metastasis via their tumor biological functions. Such transmembrane adhesion and signaling receptors are thus recognized as promising and well accessible targets for novel diagnostic and therapeutic applications for directly attacking cancer cells and their fatal microenvironment. Recently, specific small peptidic and peptidomimetic ligands as well as antibodies binding to distinct integrin subtypes have been developed and synthesized as new drug candidates for cancer treatment. Understanding the distinct functions and interplay of integrin subtypes is a prerequisite for selective intervention in integrin-mediated diseases. Integrin subtype-specific ligands labelled with radioisotopes or fluorescent molecules allows the characterization of the integrin patterns in vivo and later the medical intervention via subtype specific drugs. The coating of nanoparticles, larger proteins, or encapsulating agents by integrin ligands are being explored to guide cytotoxic reagents directly to the cancer cell surface. These ligands are currently under investigation in clinical studies for their efficacy in interference with tumor cell adhesion, migration/invasion, proliferation, signaling, and survival, opening new treatment approaches in personalized medicine.

(1) Background: Currently, there is no clinically used liquid biomarker in head and neck squamous cell carcinoma (HNSCC) patients. One reason could be the limited shedding of tumor material in early disease stages. Molecular diagnostics assessing both blood and especially saliva could potentially improve the accuracy of biomarkers. In this prospective study, two markers, tissue inhibitor of metalloprotease-1 (TIMP-1) and heat shock protein 70 (Hsp70), were analyzed in HNSCC patients. The purpose of the study was to evaluate differences between saliva and serum as sample material. Further, their prognostic and predictive value and usefulness for early detection was assessed. (2) Methods: A total of 73 HNSCC patients were prospectively monitored by collecting blood and saliva before, during, and after therapy, as well as in the follow-up period between 2018 and 2021. In total, 212 serum and 194 saliva samples were collected. A control group consisting of 40 subjects (15 patients with local infections in the head and neck area and 25 without infections) were examined as well. The collected samples were evaluated for the two proteins by using an enzyme-linked immunosorbent assay (ELISA). (3) RESULTS: The TIMP-1 concentration correlated significantly in blood and saliva, whereas the Hsp70 concentration did not. Saliva TIMP-1 was significantly higher in tumor patients compared to the control group (p = 0.013). High pretreatment TIMP-1 saliva levels were associated with significantly poorer disease-free survival (DFS) (p = 0.02). A high saliva TIMP-1/Hsp70 ratio was significantly associated with poorer DFS (HR: 1.4; 95% CI: 1.04–1.88; p = 0.026) and a high TIMP-1 serum concentration was significantly associated with poorer PFS (HR: 1.9; 95% CI: 1.2, 2.8; p = 0.003) and poorer overall survival (OS) (HR: 2.9; 95% CI: 1.4, 5.9; p = 0.003) in the Cox proportional hazards model. The saliva TIMP-1 to Hsp70 ratio was significantly higher at the time of recurrence (p = 0.015). Conclusion: TIMP-1 in serum is a promising prognostic marker for HNSCC. Saliva TIMP-1 and the saliva TIMP-1 to Hsp70 ratio provides additional information on the disease-free survival.