The Multifaceted Role of Plasminogen in Cancer

Abstract

Fibrinolytic factors like plasminogen, tissue-type plasminogen activator (tPA), and urokinase plasminogen activator (uPA) dissolve clots. Though mere extracellular-matrix-degrading enzymes, fibrinolytic factors interfere with many processes during primary cancer growth and metastasis. Their many receptors give them access to cellular functions that tumor cells have widely exploited to promote tumor cell survival, growth, and metastatic abilities. They give cancer cells tools to ensure their own survival by interfering with the signaling pathways involved in senescence, anoikis, and autophagy. They can also directly promote primary tumor growth and metastasis, and endow tumor cells with mechanisms to evade myelosuppression, thus acquiring drug resistance. In this review, recent studies on the role fibrinolytic factors play in metastasis and controlling cell-death-associated processes are presented, along with studies that describe how cancer cells have exploited plasminogen receptors to escape myelosuppression.

Keywords: LRP1; anoikis; cancer; drug resistance; exosomes; metastasis; plasminogen; premetastatic niche; senescence; uPAR.

Figure 1

The fibrinolytic spiral during cancer. In the center, the main fibrinolytic factors and their endogenous inhibitors are depicted, which are surrounded by the pathogenic mechanisms they support. The outer circle summarizes the main hallmarks of cancer described by Hannahan and Weinberg [5]. PAI-1 and PAI-2: plasminogen activator inhibitor-1 and -2, tPA: tissue-type plasminogen activator, uPA: urokinase plasminogen activator.

Figure 2

Establishment and interactions in the (pre)metastatic niche. The lower portion describes the mechanism through which fibrinolytic factors are involved in the cancer cells: autophagy through the Kringle 5 fragment or plasminogen; anoikis due to cell detachment with activation of the extrinsic apoptotic pathway through plasmin cleavage of the Fas ligand by plasmin; metastasis through pericellular plasmin activation via low-density lipoprotein receptor-related protein (LRP1) or uPA receptor (uPAR), alone or in complex with other membrane molecules (such as integrins or galectins); the participation of the senescence-associated secretory phenotype (SASP), including fibrinolytic factors like PAI-1 or PAI-2; the generation of fibrinolytic factor carrying exosomes that ensure the priming of the premetastatic niche in distant organs (such as the lung) with the establishment of the proteolytic niche. GRP78: glucose-regulated protein 78, LC3: microtubule-associated proteins 1A/1B light chain 3B, MMP: matrix metalloproteinase, PAI-1: plasminogen activator inhibitor-1, PAI-2: plasminogen activator inhibitor-2.