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. 2021 Oct 6;13(10):1625.
doi: 10.3390/pharmaceutics13101625.

Iron Oxide Nanoparticles Carrying 5-Fluorouracil in Combination with Magnetic Hyperthermia Induce Thrombogenic Collagen Fibers, Cellular Stress, and Immune Responses in Heterotopic Human Colon Cancer in Mice

Mohammad Dabaghi  1 , Seyed Mohammad Mahdi Rasa  2 , Emilio Cirri  2 , Alessandro Ori  2 , Francesco Neri  2 , Rainer Quaas  3 , Ingrid Hilger  1
Affiliations

Iron Oxide Nanoparticles Carrying 5-Fluorouracil in Combination with Magnetic Hyperthermia Induce Thrombogenic Collagen Fibers, Cellular Stress, and Immune Responses in Heterotopic Human Colon Cancer in Mice

Mohammad Dabaghi et al. Pharmaceutics. .

Abstract

In this study we looked for the main protein pathway regulators which were responsible for the therapeutic impact on colon cancers when combining magnetic hyperthermia with the chemotherapeutic agent 5-fluorouracil (5FU). To this end, chitosan-coated magnetic nanoparticles (MNP) functionalized with 5FU were intratumorally injected into subcutaneous human colon cancer xenografts (HT-29) in mice and exposed to an alternating magnetic field. A decreased tumor growth was found particularly for the combined thermo-chemotherapy vs. the corresponding monotherapies. By using computational analysis of the tumor proteome, we found upregulated functional pathway categories termed "cellular stress and injury", "intracellular second messenger and nuclear receptor signaling", "immune responses", and "growth proliferation and development". We predict TGF-beta, and other mediators, as important upstream regulators. In conclusion, our findings show that the combined thermo-chemotherapy induces thrombogenic collagen fibers which are able to impair tumor nutrient supply. Further on, we associate several responses to the recognition of damage associated molecular patterns (DAMPs) by phagocytic cells, which immigrate into the tumor area. The activation of some pathways associated with cell survival implies the necessity to conduct multiple therapy sessions in connection with a corresponding monitoring, which could possibly be performed on the base of the identified protein regulators.

Keywords: DAMPs; colon cancer; endocytosis signaling; magnetic hyperthermia; nanoparticles; thermal treatment; thrombogenic collagen fibers.

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Conflict of interest statement

The authors declare no conflicts of interest. The company had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Figures

Figure 1
Figure 1
Venn diagrams depicting the differentially expressed proteins (A), and significantly enriched canonical pathways (B) in different groups compared with the corresponding control. C: combination therapy (thermo-chemotherapy), H: hyperthermia alone, F: 5FU alone, S: short-term, L: long-term.
Figure 2
Figure 2
Top 20 significantly enriched canonical pathways of the three experimental tumor therapy arms identified using the IPA software. The length of the bars shows the −log10 of the enrichment p-value (the lower x-axis) and the black dots show the ratio of pathway-related genes differentially expressed in the indicated comparison to the total number of genes in the pathway (the upper x-axis). Colors indicate predicted activity z-score (positive values (red color) indicate activation, negative values (blue color) indicate inhibition, and gray color indicates pathways for which IPA could not predict the activity). The dashed line shows the significance threshold (log10 of 0.05). C: combination therapy (thermo-chemotherapy), H: hyperthermia alone, F: 5FU alone, L: long-term.
Figure 3
Figure 3
Heatmaps of the top 10 significantly enriched canonical pathways (short-term (A) and long-term (B) observation periods) of the three experimental tumor therapy arms identified using Table 1. of enrichment p-value. C: combination therapy (thermo-chemotherapy), H: hyperthermia alone, F: 5FU alone, S: short-term, L: long-term.
Figure 4
Figure 4
Significantly enriched canonical pathways of the functional category “cellular stress and injury” of the three experimental tumor therapy arms identified by IPA software. The height of the bars shows the −log10 of the enrichment p-value (right y-axis) and the black dots show the ratio of pathway-related genes differentially expressed in the indicated comparison to the total number of genes in the pathway (left y-axis). The colors show the predicted activity z-score (positive values (red color) indicate activation, negative values (blue color) indicate inhibition, and gray color indicates the pathways whose activity could not be predicted). The dashed line shows the significance threshold (−log10 of 0.05). C: combination therapy (thermo-chemotherapy), H: hyperthermia alone, F: 5FU alone, S: short-term, L: long-term.
Figure 5
Figure 5
Significantly enriched canonical pathways of the functional category “intracellular and second messenger signaling” of the three experimental tumor therapy arms identified by IPA software. The height of the bars shows the −log10 of the enrichment p-value (right y-axis) and the black circles show the ratio of pathway-related genes differentially expressed in the indicated comparison to the total number of genes in the pathway (left y-axis). The colors show the predicted activity z-score (positive values (red color) indicate activation, negative values (blue color) indicate inhibition, and gray color indicates the pathways whose activity could not be predicted). The dashed line shows the significance threshold (−log10 of 0.05). C: combination therapy (thermo-chemotherapy), H: hyperthermia alone, F: 5FU alone, S: short-term, L: long-term.
Figure 6
Figure 6
Significantly enriched canonical pathways of the functional category “cellular immune response” of the three experimental tumor therapy arms identified by IPA software. The height of the bars shows the −log10 of the enrichment p-value (right y-axis) and the black circles show the ratio of pathway-related genes differentially expressed in the indicated comparison to the total number of genes in the pathway (left y-axis). The colors show the predicted activity z-score (positive values (red color) indicate activation, negative values (blue color) indicate inhibition, and gray color indicates the pathways whose activity could not be predicted). The dashed line shows the significance threshold (−log10 of 0.05). C: combination therapy (thermo-chemotherapy), H: hyperthermia alone, F: 5FU alone, S: short-term, L: long-term.
Figure 7
Figure 7
Top 20 predicted upstream regulators of the three experimental therapeutic arms calculated by the IPA software. The length of the bar indicates the activity prediction z-score and colors indicate the −log10 if enrichment p-value. C: combination therapy (thermo-chemotherapy), H: hyperthermia alone, F: 5FU alone, S: short-term, L: long-term.
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