Three are better than one: plasminogen receptors as cancer theranostic targets

Abstract

Activation of plasminogen on the cell surface initiates a cascade of protease activity with important implications for several physiological and pathological events. In particular, components of the plasminogen system participate in tumor growth, invasion and metastasis. Plasminogen receptors are in fact expressed on the cell surface of most tumors, and their expression frequently correlates with cancer diagnosis, survival and prognosis. Notably, they can trigger multiple specific immune responses in cancer patients, highlighting their role as tumor-associated antigens. In this review, three of the most characterized plasminogen receptors involved in tumorigenesis, namely Annexin 2 (ANX2), Cytokeratin 8 (CK8) and alpha-Enolase (ENOA), are analyzed to ascertain an overall view of their role in the most common cancers. This analysis emphasizes the possibility of delineating new personalized therapeutic strategies to counteract tumor growth and metastasis by targeting plasminogen receptors, as well as their potential application as cancer predictors.

Blockade of Surface Alpha-Enolase (ENO1) as a Novel Immunotherapeutic Approach in Pancreatic Cancer

“…By promoting plasminogen activation into plasmin, a serine-protease involved in extracellular matrix degradation, ENO1 favors cell invasion and metastasis (Figure1 upper panel) [9]. The plasminogen system is involved in tumor growth, invasion and metastasis [12]. Several proteins of this system have been demonstrated to have a clinical value as diagnostic and prognostic markers in cancer.…”

“…Several proteins of this system have been demonstrated to have a clinical value as diagnostic and prognostic markers in cancer. In particular, overexpression of plasminogen receptors has been associated with poor prognosis, shorter survival and resistance to chemotherapy [12].…”

“…This observation suggests that spreading and invasion of PDA cells is strictly related to the high cell surface expression of ENO1, which, in turn, facilitates binding of elevated concentrations of plasminogen at the cell surface. Plasminogen is cleaved into plasmin by uPA (urokinase plasminogen activator), resulting in an increased ability of PDA cells to degrade the ECM [12]. We targeted surface ENO1 by using a mouse monoclonal antibody (mAb) that blocks the plasminogen-ENO1 interaction [13].…”

Phosphorylated alpha-enolase induces autoantibodies in HLA-DR8 pancreatic cancer patients and triggers HLA-DR8 restricted T-cell activation

“…ENOA is a moonlighting protein that works both as a glycolytic enzyme and as a membrane plasminogen receptor, thus promoting tumor proliferation, spreading and metastasis [4,5]. In particular, a fraction of PDAC patients specifically produce autoantibodies against two Ser 419 phosphorylated isoforms of ENOA (ENOA1,2), which are over-expressed in PDAC [3,4,6,7].…”

“…Depending on the position within the peptide, phosphorylation tends to stabilize the complex, without greatly altering the peptide-binding mode. 5 The prognostic value of autoantibodies to ENOA1,2, together with the ability of ENOA to induce a specific CD4 + T cell response, led us to investigate whether the ability to produce autoantibodies against ENOA1,2, in PDAC patients, is associated with specific HLA-DRB1 alleles. Here, we demonstrate that expression of the HLA-DRB1*08 allele is greater in PDAC patients with autoantibodies to ENOA1,2 compared to healthy controls or patients lacking these antibodies.…”