Cellular Oncology

, Volume 42, Issue 2, pp 173–196 | Cite as

Secretome profiling of heterotypic spheroids suggests a role of fibroblasts in HIF-1 pathway modulation and colorectal cancer photodynamic resistance

  • María Julia Lamberti
  • Mandy Rettel
  • Jeroen Krijgsveld
  • Viviana Alicia RivarolaEmail author
  • Natalia Belén Rumie VittarEmail author
Original Paper



Previous analyses of the tumor microenvironment (TME) have resulted in a concept that tumor progression may depend on interactions between cancer cells and its surrounding stroma. An important aspect of these interactions is the ability of cancer cells to modulate stroma behavior, and vice versa, through the action of a variety of soluble mediators. Here, we aimed to identify soluble factors present in the TME of colorectal cancer cells that may affect relevant pathways through secretome profiling.


To partially recapitulate the TME and its architecture, we co-cultured colorectal cancer cells (SW480, TC) with stromal fibroblasts (MRC-5, F) as 3D-spheroids. Subsequent characterization of both homotypic (TC) and heterotypic (TC + F) spheroid secretomes was performed using label-free liquid chromatography-mass spectrometry (LC-MS).


Through bioinformatic analysis using the NCI-Pathway Interaction Database (NCI-PID) we found that the HIF-1 signaling pathway was most highly enriched among the proteins whose secretion was enhanced in the heterotypic spheroids. Previously, we found that HIF-1 may be associated with resistance of colorectal cancer cells to photodynamic therapy (PDT), an antitumor therapy that combines photosensitizing agents, O2 and light to create a harmful photochemical reaction. Here, we found that the presence of fibroblasts considerably diminished the sensitivity of colorectal cancer cells to photodynamic activity. Although the biological significance of the HIF-1 pathway of secretomes was decreased after photosensitization, this decrease was partially reversed in heterotypic 3D-spheroids. HIF-1 pathway modulation by both PDT and stromal fibroblasts was confirmed through expression assessment of the HIF-target VEGF, as well as through HIF transcriptional activity assessment.


Collectively, our results delineate a potential mechanism by which stromal fibroblasts may enhance colorectal cancer cell survival and photodynamic treatment resistance via HIF-1 pathway modulation.


Tumor microenvironment Photodynamic therapy Secretome Spheroids Cancer associated fibroblasts Colorectal cancer cells 



Three dimensional


Automatic gain control


Colorectal cancer


Dimethyl sulfoxide


Enolase 1




Fetal bovine serum


Green fluorescent protein


Glucose transporter 1


High energy collision induced dissociation


Hypoxia inducible factor-1


Lactate dehydrogenase


Liquid chromatography–Mass spectrometry


Label-free quantification


Aminolevulinic acid methyl ester




National Cancer Institute–Pathway Interaction Database




Plasminogen activator inhibitor 1


Phosphate buffer saline


Protoporphyrin IX




Tumor cell


Transferrin receptor protein 1


Vascular endothelial growth factor



This work was supported by grants from the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Agencia Nacional de Promoción Científica y Tecnológica (PICT), Secretaría de Ciencia y Técnica (SECyT), Universidad Nacional de Río Cuarto, and a Christian Boulin Fellowship (EMBL). VAR and NBRV are members of the Scientific Researcher Career at CONICET. MJL holds a fellowship from CONICET.

Compliance with ethical standards

Conflict of interest

None declared.

Supplementary material

13402_2018_418_MOESM1_ESM.docx (20 kb)
Table S1 Perseus correlation matrix. Correlation coefficients whose magnitude were greater than 0.7 were considered highly correlated (red numbers indicate correlation values <0.7) (DOCX 19 kb)
13402_2018_418_MOESM2_ESM.docx (33 kb)
Table S2 List of proteins identified in homotypic spheroids secretome. Available information: ID identified according to UniProt, name of the protein, corresponding gene, location of the signal peptide in those proteins secreted by the classical pathway (SignalP), NN-score of proteins secreted by non-classical pathways (SecretomeP, the NN-score should be greater than 0.5), LFQ (“label-free quantification”) value (mean and standard deviation). (DOCX 33 kb)
13402_2018_418_MOESM3_ESM.docx (37 kb)
Table S3 List of proteins identified in heterotypic spheroids secretome. Available information: ID identified according to UniProt, name of the protein, corresponding gene, location of the signal peptide in those proteins secreted by the classical pathway (SignalP), NN-score of proteins secreted by non-classical pathways (SecretomeP, the NN-score should be greater than 0.5), LFQ (“label-free quantification”) value (mean and standard deviation). (DOCX 36 kb)
13402_2018_418_MOESM4_ESM.docx (45 kb)
Table S4 List of proteins identified in PDT-treated homotypic spheroids secretome. Available information: ID identified according to UniProt, name of the protein, corresponding gene, location of the signal peptide in those proteins secreted by the classical pathway (SignalP), NN-score of proteins secreted by non-classical pathways (SecretomeP, the NN-score should be greater than 0.5), LFQ (“label-free quantification”) value (mean and standard deviation). (DOCX 45 kb)
13402_2018_418_MOESM5_ESM.docx (55 kb)
Table S5 List of proteins identified in PDT-treated heterotypic spheroids secretome. Available information: ID identified according to UniProt, name of the protein, corresponding gene, location of the signal peptide in those proteins secreted by the classical pathway (SignalP), NN-score of proteins secreted by non-classical pathways (SecretomeP, the NN-score should be greater than 0.5), LFQ (“label-free quantification”) value (mean and standard deviation). (DOCX 55 kb)
13402_2018_418_MOESM6_ESM.jpg (64 kb)
Fig S1 Histograms. Histograms were performed using the logarithmic LFQ values (log10 (x)) to visualize the normal distribution of the data (Perseus software) (JPG 63 kb)
13402_2018_418_MOESM7_ESM.jpg (221 kb)
Fig S2 Multiscatter plot. The multiscatter plot was performed using the logarithmic LFQ values (log2 (x)) to visualize the correlation between the replicates (JPG 220 kb)
13402_2018_418_Fig6_ESM.png (981 kb)
Fig S3

Gene Ontology. (A) Biological process classification in Gene Ontology analysis of proteins whose secretion was enhanced in in photosensitized homotypic spheroids compared to untreated ones. (B) Biological process classification in Gene Ontology analysis of proteins whose secretion was enhanced in in photosensitized heterotypic spheroids compared to untreated ones. (PNG 980 kb)

13402_2018_418_MOESM8_ESM.tif (11.6 mb)
High Resolution (TIF 11850 kb)


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Copyright information

© International Society for Cellular Oncology 2019

Authors and Affiliations

  • María Julia Lamberti
    • 1
  • Mandy Rettel
    • 2
  • Jeroen Krijgsveld
    • 2
    • 3
  • Viviana Alicia Rivarola
    • 1
    Email author
  • Natalia Belén Rumie Vittar
    • 1
    Email author
  1. 1.Departamento de Biología Molecular, Facultad de Ciencias Exactas Físico-Químicas y NaturalesUniversidad Nacional de Río CuartoRío CuartoArgentina
  2. 2.European Molecular Biology Laboratory (EMBL)HeidelbergGermany
  3. 3.German Cancer Research Center (DKFZ)HeidelbergGermany

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