Communication Breakdown: How Cancer Hijacks Cell Signaling Pathways

Communication Breakdown: How Cancer Hijacks Cell Signaling Pathways Laura Hemmingham, PhD The human body contains around 30–40 trillion cells in constant conversation with each other and their environment. They communicate through signaling pathways, a series of chemical reactions that allow cells to send messages following environmental cues. The topics of their conversation might include when to grow, repair or die. Cancer cells develop when these signaling pathways become hijacked, causing breakdowns in communication and creating an environment in which they can thrive. This includes uncontrolled growth, unsolicited movement around the body and evading cell death.1 By studying how cell signaling goes wrong, scientists have transformed the way we fight cancer. Steering away from general and toxic treatments such as chemotherapy to focus on cell signaling enables the development of specialized therapies that block corrupted pathways, restore immune surveillance and even predict resistance before it happens. This listicle presents six insights that reveal how cancer manipulates the body’s messaging systems and how this knowledge is shaping medical advancements. 1. How does cancer develop? Cell networks are in constant communication. With trillions of cells in our body, a comparable number of messages are sent per second. When cancer occurs, these messages are corrupted, allowing tumors to grow and evade destruction. Growth factors are molecules that stimulate cell division when the environment is suitable, while tumor suppressors act in tandem to halt growth when something appears to be wrong. The protein p53 is perhaps the most famous tumor suppressor in this system, nicknamed the “guardian of the genome” for its ability to pause repairs or trigger cell death when damage is beyond repair (Table 1).2 Table 1. A comparison of the functions of normal p53 in healthy cells and mutated p53 in cancer cells. In mutated cells, these functions are blocked and uncontrolled growth occurs. Healthy cell (normal p53) Cell cycle arrest DNA repair Apoptosis Senescence ✓ ✓ Cancer cell (mutated p53) ✓ ✓ x x x x 1 Listicle Cancer develops when this sophisticated network is hacked. During this process, proto-oncogenes encoding growth factors are mutated, becoming oncogenes, which are stuck in overdrive. Tumor suppressors, which act as brakes, become silenced or deleted. These failures in healthy cell signaling allow the conversion of cooperative cells into cells that selfishly promote their survival over others.1 Instead of following the usual cell lifecycle, cancerous cells keep dividing, consuming resources and ultimately transform into tumors. 2. The three core pathways exploited by cancer Cancer can affect multiple signaling pathways simultaneously. Yet, three pathways are primary targets and confer cancer cells with their most deadly traits – uncontrolled growth, evading apoptosis and spreading around the body. The first is the MAPK/ERK pathway. This pathway regulates a range of cellular processes, including growth, differentiation, death and stress responses. Much of this activity is controlled by Ras proteins – molecular switches that turn on and off such activity. In approximately 30% of cancers, Ras proteins are locked in the “on” position, leading to increased cell proliferation.3 The second is the PI3K/AKT pathway, which regulates cell survival. This system controls whether cells undergo apoptosis under environmental stress. This pathway is altered in cancer cells, often through the disruption of PTEN, a gene that induces apoptosis. Consequently, even damaged cells continue living. The disruption of this pathway also has huge consequences for therapies. For instance, chemotherapy works by triggering apoptosis, so the cells with PI3K/AKT pathway mutations may not respond to the treatment.4 Lastly, the Wnt/β-catenin signaling pathway informs the cell of its location and identity. In healthy stem cells, this pathway gives cells the ability to renew themselves and controls their development into the right cell types in the right places. When the pathway is faulty, cells may continue dividing, growing tumors and spreading around the body.5 3. How cancer spreads Metastasis, the spread of cancer, is reported to be the cause of most cancer-related deaths. Depending on cancer type, metastases can contribute to death in up to 90% of cases.6 Achieving metastasis is no easy task for a cancer cell, as it requires numerous changes that allow the cell to change form, escape from surrounding tissue and find a new home elsewhere in the body. The first stage involves acquiring the ability to move. Most cells, especially epithelial cells that line organs, are designed to stay in place. To bypass this characteristic, cancer cells undergo epithelialmesenchymal transition (EMT). During this transition, EMT-associated transcription factors (EMT-TFs) silence epithelial genes such as E-cadherin, which causes cells to lose their “glue” that sticks them to neighboring cells. EMT-TFs also turn on mesenchymal genes such as VIM, which encodes vimentin, providing the cell with mobility.7 Once cancer cells can move freely, they need to be able to escape their immediate surroundings. After attaching to the basement membrane, which is the barrier between epithelia and vascular structures within the stroma, cancer cells can secrete degradative enzymes to pave a microscopic pathway through the surrounding extracellular matrix.8 With access to the bloodstream, cancer cells can travel and invade other tissues around the body. Tumor cells prepare future metastatic sites by recruiting bone marrow-derived cells (BMDCs) and reshaping the microenvironment into a supportive pre-metastatic niche, enabling them to settle, survive and grow into new tumors. BMDCs remodel tissue, suppressing immunity and promoting angiogenesis, creating a fertile environment for the arriving metastatic tumor cells.9 COMMUNICATION BREAKDOWN: HOW CANCER HIJACKS CELL SIGNALING PATHWAYS 2 Listicle 4. Acquiring accomplices The disruption cancer causes goes beyond cell signaling. Tumors manipulate the entire environment around them, from creating tissue barriers and bypassing immune attacks to acquiring their own blood supply.10-12 For instance, fibroblasts that build and maintain connective tissues become hijacked, releasing growth factors that remodel tissue barriers and create structures that protect tumors from drugs and immune attacks.10 Further protection from immune recognition involves tumor cells expressing proteins such as PD-L1. Usually, healthy cells use this protein to signal to T cells that they shouldn’t attack them. Tumors also express this protein, preventing the immune system from destroying them.11 In order to create their own blood supply, tumors release vascular endothelial growth factor, eliciting angiogenesis.12 Not only does this new vasculature provide essential nutrients and oxygen that support tumor growth, it also provides a convenient pathway back out into the wider circulatory system. 5. How modern medicine is fighting back The understanding of specific downstream processes affected by cancer has initiated the development of targeted treatments. Targeted small-molecule drugs have dramatically transformed treatment options. For instance, the small molecule inhibitor imatinib mesylate that targets the causative Bcr-Abl oncoprotein (a fusion protein driving cancer) is being successfully used to treat chronic myeloid leukemia.13 Similar therapies exist for specific oncoproteins involved in a range of cancers, including melanoma, lung and breast cancer. Another breakthrough is immunotherapy. Drugs called checkpoint inhibitors allow T cells to recognize and attack tumor cells that once evaded them, while CAR T-cell therapy genetically engineers a patient’s own immune cells to recognize and attack cancer.14 Although these intuitive advancements have afforded remission for countless patients, the treatments are not infallible. Cancer can adapt by finding alternative pathways or overcoming blocked targets, forming resistance to current treatment efforts. Consequently, drug development is in constant demand, while liquid biopsies – simple blood tests detecting tumor DNA – allow doctors to spot resistance early and adjust treatments in real time. 6. The future of cancer treatment New technological advancements are powering research, and cancer is no exception. The use of artificial intelligence (AI) is expediting cancer research discoveries. By combing through mountains of genetic and clinical data, AI can indicate which drugs a tumor will respond to, predict patient outcomes, uncover hidden targets and even design new medicines. It’s also transforming imaging, relieving workloads and detecting subtle cancer features invisible to the human eye. Single-cell analysis has revealed that tumors are not uniform but mosaics of diverse cell types with varied responses to drugs.15 Organoid models – tiny replicas of patient tumors grown in labs – allow doctors to test drugs before trying them in patients, pointing toward personalized therapies. COMMUNICATION BREAKDOWN: HOW CANCER HIJACKS CELL SIGNALING PATHWAYS 3 Listicle Together, these tools are bringing personalized medicine closer to reality. Predictive models, multiomic profiling and 3D cell culture models allow doctors to tailor treatments to each patient’s unique tumor characteristics and adapt them as the disease evolves. Stopping cancer in its tracks Cancer thrives on hijacking the ability of cells to effectively communicate and control their own proliferation and survival, turning a once harmonious environment into one solely for cancer’s gain. However, with an evolving understanding of how cancer truly operates, scientists can better develop personalized and targeted treatment options that stop cancer with increasingly more precision and improve patient outcomes. References 1. Weinberg RA. How cancer arises. Sci Am. 1996;275(3):62-70. doi: 10.1038/scientificamerican0996-62 2. Feroz W, Sheikh AMA. Exploring the multiple roles of guardian of the genome: P53. Egypt J Med Hum Genet. 2020;21:49. doi: 10.1186/s43042-020-00089-x 3. Guo YJ, Pan WW, Liu SB, Shen ZF, Xu Y, Hu LL. ERK/MAPK signalling pathway and tumorigenesis (Review). Exp Ther Med. 2020;19(3):1997–2007. doi: 10.3892/etm.2020.8454 4. Fresno Vara JÁ, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004;30(2):193–204. doi: 10.1016/j.ctrv.2003.07.007 5. Zhang Y, Wang X. Targeting the Wnt/β-catenin signaling pathway in cancer. J Hematol Oncol. 2020;13:165. doi: 10.1186/ s13045-020-00990-3 6. Dillekås H, Rogers MS, Straume O. Are 90% of deaths from cancer caused by metastases? Cancer Med. 2019;8(12):55745576. doi: 10.1002/cam4.2474 7. Huang Z, Zhang Z, Zhou C, Liu L, Huang C. Epithelial–mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities. MedComm. 2022;3(2):e144. doi: 10.1002/mco2.144 8. Herszényi L, Barabás L, Hritz I, István G, Tulassay Z. Impact of proteolytic enzymes in colorectal cancer development and progression. World J Gastroenterol. 2014;20(37):13246–13257. doi: 10.3748/wjg.v20.i37.13246 9. Wang Y, Jia J, Wang F, et al. Pre-metastatic niche: formation, characteristics and therapeutic implication. Signal Transduct Target Ther. 2024;9:236. doi: 10.1038/s41392-024-01937-7 10. Yang D, Liu J, Qian H, Zhuang Q. Cancer-associated fibroblasts: from basic science to anticancer therapy. Exp Mol Med. 2023;55(7):1322–1332. doi: 10.1038/s12276-023-01013-0 11. Cha J-H, Chan L-C, Li C-W, Hsu JL, Hung M-C. Mechanisms Controlling PD-L1 Expression in Cancer. Mol Cell. 2019;76(3):359–370. doi: 10.1016/j.molcel.2019.09.030 12. Kut C, Mac Gabhann F, Popel AS. Where is VEGF in the body? A meta-analysis of VEGF distribution in cancer. Br J Cancer. 2007;97(7):978–985. doi: 10.1038/sj.bjc.6603923 13. Henkes M, van der Kuip H, Aulitzky WE. Therapeutic options for chronic myeloid leukemia: focus on imatinib (Glivec®, Gleevec™). Ther Clin Risk Manag. 2008;4:163–187. doi: 10.2147/tcrm.s12160500 14. Ali S, Arshad M, Summer M. Recent developments on checkpoint inhibitors, CAR T cells, and beyond for T cell-based immunotherapeutic strategies against cancer. J Oncol Pharm Pract. 2025;31(7):1115–1144. doi: 10.1002/jcb.202300096 15. Gambardella G, Viscido G, Tumaini B, Isacchi A, Bosotti R, di Bernardo D. A single-cell analysis of breast cancer cell lines to study tumour heterogeneity and drug response. Nat Commun. 2022;13(1):1714. doi: 10.1038/s41467-022-29358-6 Sponsored by: About the author: Laura Hemmingham is a scientific content producer for Technology Networks. She holds a PhD in Environmental Sciences from Royal Holloway, University of London. Her academic journey has been fueled by a broad interest in the life sciences and her work aims to support scientific literacy while highlighting the real-world impact of research and innovation. COMMUNICATION BREAKDOWN: HOW CANCER HIJACKS CELL SIGNALING PATHWAYS