Exploring the cell-to-cell communication network to better defeat cancer

Just like us, cells communicate, but in their own unique way. Using waves as their common language, cells signal to each other about where and when to move. They talk, share information, and collaborate. The human body comprises trillions of cells that continuously adapt to their surroundings, exchanging millions of vital signals for survival. This communication must be meticulously regulated, as any disruption can lead to errors, such as the abnormal cell growth observed in cancer. The interaction between cancer cells and their neighboring cells is bidirectional, involving a complex network of mechanisms that can drive aggressive tumor behaviors—such as rapid growth, spread, and treatment resistance—or, conversely, act to suppress malignancy. This dynamic interplay within the tumor microenvironment unfolds through two primary modes: direct communication through physical cell contact, mediated by adhesion molecules, electrical signals, or the exchange of materials through gap junctions, and indirect communication facilitated by paracrine signaling. The latter involves the release of signaling molecules like cytokines, growth factors, and extracellular vesicles. Disrupting these cellular dialogues presents a promising therapeutic frontier. Specifically, strategies that integrate interventions targeting tumor communication pathways with conventional chemotherapy could enhance treatment efficacy, offering a synergistic approach to hinder cancer progression and improve outcomes. This article delves into the role of cell-to-cell communication in cancer development, its impact on metastasis, and how ongoing research is broadening our understanding of the disease.
- Su J, Song Y, Zhu Z, et al. Cell-cell communication: New insights and clinical implications. Signal Transduct Target Ther. 2024;9:196. doi: 10.1038/s41392-024-01888-z
- Chiodoni C, Di Martino MT, Zazzeroni F, et al. Cell communication and signaling: How to turn bad language into positive one. J Exp Clin Cancer Res. 2019;38(1):128. doi: 10.1186/s13046-019-1122-2
- Dimitrov D, Türei D, Garrido-Rodriguez M, et al. Comparison of methods and resources for cell-cell communication inference from single-cell RNA-Seq data. Nat Commun. 2022;13(1):3224. doi: 10.1038/s41467-022-30755-0
- Shao X, Lu X, Liao J, Chen H, Fan X. New avenues for systematically inferring cell-cell communication: Through single-cell transcriptomics data. Protein Cell. 2020;11(12):866-880. doi: 10.1007/s13238-020-00727-5
- Ginini L, Billan S, Fridman E, Gil Z. Insight into extracellular vesicle-cell communication: From cell recognition to intracellular fate. Cells. 2022;11(9):1375. doi: 10.3390/cells11091375
- Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178-196. doi: 10.1038/nrm3758
- Wheelock MJ, Shintani Y, Maeda M, Fukumoto Y, Johnson KR. Cadherin switching. J Cell Sci. 2008;121(Pt 6): 727-735. doi: 10.1242/jcs.000455
- Guilford P. E-cadherin downregulation in cancer: Fuel on the fire? Mol Med Today. 1999;5(4):172-177. doi: 10.1016/s1357-4310(99)01461-6
- Wei C, Yang C, Wang S, et al. Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis. Mol Cancer. 2019;18(1):64. doi: 10.1186/s12943-019-0976-4
- Huang S, Chaudhary K, Garmire LX. More is better: Recent progress in multi-omics data integration methods. Front Genet. 2017;8:84. doi: 10.3389/fgene.2017.00084
- Yan H, Deng X, Chen H, et al. Identification of common and subtype-specific mutated sub-pathways for a cancer. Front Genet. 2019;10:1228. doi: 10.3389/fgene.2019.01228
- Griffiths JI, Cosgrove PA, Castaneda EM, et al. Cancer Cells Communicate with Macrophages to Prevent T Cell Activation During Development of Cell Cycle Therapy Resistance. BioRxiv [Preprint]; 2022. doi: 10.1101/2022.09.14.507931
- Coursier D, Calvo F. CAFs vs. TECs: When blood feuds fuel cancer progression, dissemination and therapeutic resistance. Cell Oncol (Dordr). 2024;47(4):1091-1112. doi: 10.1007/s13402-024-00931-z
- Bach K, Pensa S, Zarocsinceva M, et al. Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors. Nat Commun. 2021;12:1502. doi: 10.1038/s41467-021-21783-3
- Alonso-Curbelo D, Ho YJ, Burdziak C, et al. A gene-environment-induced epigenetic program initiates tumorigenesis. Nature. 2021;590:642-648. doi: 10.1038/s41586-020 03147-x
- Denk D, Greten FR. Inflammation: The incubator of the tumor microenvironment. Trends Cancer. 2022;8:901-914. doi: 10. 1016/j.trecan.2022.07.002
- Ringel AE, Drijvers JM, Baker GJ, et al. Obesity shapes metabolism in the tumor microenvironment to suppress anti-tumor immunity. Cell. 2020;183:1848-1866.e26. doi: 10.1016/j.cell.2020.11.009
- Philip M, Schietinger A. CD8+ T cell differentiation and dysfunction in cancer. Nat Rev Immunol. 2022;22:209-223. doi: 10.1038/s41577-021-00574-3
- Zheng L, Qin S, Si W, et al. Pan-cancer single-cell landscape of tumor-infiltrating T cells. Science. 2021;374:abe6474. doi: 10.1126/science.abe6474
- Han C, Zhang C, Wang H, Zhao L. Exosome-mediated communication between tumor cells and tumor-associated macrophages: Implications for tumor microenvironment. Oncoimmunology. 2021;10(1):1887552. doi: 10.1080/2162402X.2021.1887552
- Nicolini A, Paola F, Biava PM. Exosomes and cell communication: From tumour-derived exosomes and their role in tumour progression to the use of exosomal cargo for cancer treatment. Cancers (Basel). 2021;13(4):822. doi: 10.3390/cancers13040822
- Kalluri R. The biology and function of exosomes in cancer. J Clin Invest. 2016;126(4)1208-1215. doi: 10.1172/JCI81135
- Kharaziha P, Ceder S, Li Q, Panaretakis T. Tumor cell-derived exosomes: A message in a bottle. Biochim Biophys Acta. 2012;1826:103-111. doi: 10.1016/j.bbcan.2012.03.006
- Nogués L, Benito-Martin A, Hergueta-Redondo M, Peinado H. The influence of tumour-derived extracellular vesicles on local and distal metastatic dissemination. Mol Aspects Med. 2018;60:15-26. doi: 10.1016/j.mam.2017.11.012
- Maia J, Caja S, Strano Moraes MC, Couto N, Costa-Silva B. Exosome-based cell-cell communication in the tumor microenvironment. Front Cell Dev Biol. 2018;6:18. doi: 10.3389/fcell.2018.00018
- Liu SL, Sun P, Li Y, Liu SS, Lu Y. Exosomes as critical mediators of cell-to-cell communication in cancer pathogenesis and their potential clinical application. Transl Cancer Res. 2019;8(1):298-311. doi: 10.21037/tcr.2019.01.03
- Fares J, Fares MY, Khachfe HH, Salhab HA, Fares Y. Molecular principles of metastasis: A hallmark of cancer revisited. Signal Transduct Target Ther. 2020;5:28. doi: 10.1038/s41392-020-0134-x
- Aizaz M, Khan A, Khan F, et al. The cross-talk between macrophages and tumor cells as a target for cancer treatment. Front Oncol. 2023;13:1259034. doi: 10.3389/fonc.2023.1259034
- Vesely MD, Schreiber RD. Cancer immunoediting: Antigens, mechanisms and implications to cancer immunotherapy. Ann N Y Acad Sci. 2013;1284(1):1-5. doi: 10.1111/nyas.12105
- Nasr MM, Lynch CC. How circulating tumor cluster biology contributes to the metastatic cascade: From invasion to dissemination and dormancy. Cancer Metastasis Rev. 2023;42(4):1133-1146. doi: 10.1007/s10555-023-10124-z
- Schuster E, Taftaf R, Reduzzi C, Albert MK, Romero-Calvo I, Liu H. Better together: Circulating tumor cell clustering in metastatic cancer. Trends Cancer. 2021;7(11):1020-1032. doi: 10.1016/j.trecan.2021.07.001
- Bouchalova P, Bouchal P. Current methods for studying metastatic potential of tumor cells. Cancer Cell Int. 2022;22:394. doi: 10.1186/s12935-022-02801-w
- Horne J, Mansur S, Bao Y. Sodium ion channels as potential therapeutic targets for cancer metastasis. Drug Discov Today. 2021;26(5):1136-1147. doi: 10.1016/j.drudis.2021.01.026
- Rahrmann EP, Shorthouse D, Jassim A, et al. The NALCN channel regulates metastasis and nonmalignant cell dissemination. Nat Genet. 2022;54(12):1827-1838. doi: 10.1038/s41588-022-01182-0
- Emancipator K. Keytruda and PD-L1: A real-world example of co-development of a drug with a predictive biomarker. AAPS J. 2020;23(1):5. doi: 10.1208/s12248-020-00525-1
- Abad-Sazatornil MR, Arenaza A, Bayo J, et al. Impact of the subcutaneous formulations of trastuzumab and rituximab on efficiency and resource optimization in Spanish Hospitals: H-Excelencia study. BMC Health Serv Res. 2021; 21(1):320. doi: 10.1186/s12913-021-06277-8
- Sterner RC, Sterner RM. CAR-T cell therapy: Current limitations and potential strategies. Blood Cancer J. 2021;11(4):69. doi: 10.1038/s41408-021-00459-7
- Waters EA, McNeel TS, Stevens WM, Freedman AN. Use of tamoxifen and raloxifene for breast cancer chemoprevention in 2010. Breast Cancer Res Treat. 2012;134(2):875-880. doi: 10.1007/s10549-012-2089-2
- Sini V, Botticelli A, Lunardi G, Gori S, Marchetti P. Pharmacogenetics and aromatase inhibitor induced side effects in breast cancer patients. Pharmacogenomics. 2017;18(8):821-830. doi: 10.2217/pgs-2017-0006