Local Production of Acute Phase Proteins: A Defense Reaction of Cancer Cells to Injury with Focus on Fibrinogen

Abstract

This review is intended to demonstrate that the local production of acute phase proteins (termed local acute phase response (lAPR)) and especially fibrin/fibrinogen (FN) is a defense mechanism of cancer cells to therapy, and inhibition of the lAPR can augment the effectiveness of cancer therapy. Previously we detected a lAPR accompanying tumor cell death during the treatment of triple-negative breast cancer (TNBC) with modulated electro-hyperthermia (mEHT) in mice. We observed a similar lAPR in in hypoxic mouse kidneys. In both models, production of FN chains was predominant among the locally produced acute phase proteins. The production and extracellular release of FN into the tumor microenvironment is a known method of self-defense in tumor cells. We propose that the lAPR is a new, novel cellular defense mechanism like the heat shock response (HSR). In this review, we demonstrate a potential synergism between FN inhibition and mEHT in cancer treatment, suggesting that the effectiveness of mEHT and chemotherapy can be enhanced by inhibiting the HSR and/or the lAPR. Non-anticoagulant inhibition of FN offers potential new therapeutic options for cancer treatment.

Keywords: fibrinogen (FN); local acute phase response (lAPR) cancer; modulated electrohyperthermia (mEHT); tumor microenvironment (TME).

Figure 2

(A) Fibrin(ogen) surrounding tumor cells produced by the cancer cells themselves or platelets in the TME aids the formation of protective tumor microenvironment. The deposited fibrin may stimulate proinflammatory processes in the TME by recruiting and activating leucocytes. Fibrin filtered from permeable blood vessels and deposited around them aid the vascular entrance of potentially metastatic cells [26]. (B) Drugability of the fibrinolysis pathways. Top upregulated proteins (blue) in our mouse model were related to fibrin(ogen) deposition and degradation. (tPA: tissue plasminogen activator [58], PAI: plasminogen activator inhibitor, SPA3K: serine protease inhibitor (Serpin)-A3 = alpha-1-anitchymotrypsin). Current possibilities for intervention (green labels) and diseases where these interventions are used clinically (green letters) are indicated. (ACS: acute coronary syndrome, PE: pulmonary embolism, tPA: tissue plasminogen activator [59]: direct thrombin inhibitor (dabigatran), SPK: Spa3K inhibitor developed by Spark Therapeutics [60]. The figures were created with Biorender.com.

Figure 1

Multiplex analysis of mEHT treated TNBC samples. (A) Next generation sequencing (NGS) results of mEHT- vs. sham-treated tumors (heat map: red: up-, green: down-regulated genes). (B) Volcano plot of the NGS data: the most upregulated proteins were acute phase proteins (red dots and numbers). (C) NanoString verified acute phase protein upregulation [4].