Mesothelioma cells originate from the mesothelium, a thin tissue lining the chest, abdomen, and heart, when prolonged exposure to asbestos or certain other mineral fibers triggers genetic damage that turns normal lining cells into aggressively dividing tumor cells. What makes these cells particularly difficult to treat is a combination of factors: they come in several distinct forms, they recruit surrounding immune cells to shield them from attack, they harbor mutations in tumor-suppressor genes that are hard to target with conventional drugs, and a small subpopulation of stem-like cells can survive chemotherapy and seed recurrence. Understanding the biology of these cells has become the central challenge in improving outcomes for a cancer that still carries a median survival measured in months.
How Normal Mesothelial Cells Become Cancerous
The mesothelium is made up of flat cells that produce a lubricating fluid, allowing organs to slide against each other during breathing and digestion. When asbestos fibers are inhaled or swallowed, some of them work their way to these lining tissues and become lodged there. The fibers are too long and durable for the body’s cleanup crew to fully digest, so mesothelial cells attempt to engulf them. That act of engulfment triggers a cascade of oxidative stress and DNA damage inside the cell.1American Journal of Respiratory Cell and Molecular Biology. Phagocytosis of Crocidolite Asbestos Induces Oxidative Stress, DNA Damage, and Apoptosis in Mesothelial Cells Over years or even decades, repeated cycles of damage and repair accumulate mutations that eventually disable the cell’s built-in growth brakes, and a tumor begins to form.
Asbestos is not the only culprit. Erionite, a naturally occurring fibrous mineral found in volcanic rock in parts of Turkey, the western United States, and elsewhere, has mesothelioma-causing potency equal to or greater than that of asbestos.2Annals of Work Exposures and Health. 54 Erionite-induced carcinogenicity: mechanistic insights and comparative potency with asbestos In laboratory studies, long-term erionite exposure transforms human mesothelial cells into highly proliferating, cancerous cells on its own, without requiring additional co-factors.3PubMed. Erionite and asbestos differently cause transformation of human mesothelial cells Erionite works somewhat differently from asbestos: rather than mainly killing cells and forcing error-prone repair cycles, it stimulates proliferating signals and a high growth rate, pushing cells toward transformation through sheer runaway division.4PubMed. Patterns of c-fos and c-jun proto-oncogene expression, apoptosis, and proliferation in rat pleural mesothelial cells exposed to erionite or asbestos fibers
There has also been long-running debate about whether a monkey virus called SV40 contributes. SV40 contaminated some polio vaccines in the mid-twentieth century and can infect and transform human mesothelial cells in the lab. In animal experiments, SV40 and asbestos together produce mesothelioma more readily than either agent alone.5PubMed Central. SV40 and human mesothelioma Still, the fact that there was no epidemic of mesothelioma among the millions of people who received contaminated vaccines suggests SV40 alone is not enough to cause the disease; it may act as a co-factor in some cases rather than a primary driver.6PubMed Central. Simian virus 40 transformation, malignant mesothelioma and brain tumors
The Genetic Wiring That Keeps Mesothelioma Cells Growing
Three tumor-suppressor genes turn up mutated or deleted again and again in mesothelioma: BAP1, NF2, and CDKN2A. Each one normally acts as a different kind of brake on cell growth. When all three are knocked out together, the result is explosive. In mouse models where researchers disabled all three genes in the mesothelial lining, tumors appeared in about 85% of animals and did so in roughly 12 weeks, compared with 27 weeks when only two of the three were lost.7PubMed Central. Inactivation of Bap1 Cooperates with Losses of Nf2 and Cdkn2a to Drive the Development of Pleural Malignant Mesothelioma in Conditional Mouse Models The triple-knockout tumors were consistently high-grade, invasive, and fast-growing, and some of the cells displayed stem-cell-like features, forming floating spheroids in culture.
Independent work confirmed this picture. When researchers disrupted all three genes in the mouse thoracic lining, the resulting aggressive tumors closely matched human mesothelioma in both tissue architecture and gene-expression patterns.8Journal of Experimental Medicine. Combined deletion of Bap1, Nf2, and Cdkn2ab causes rapid onset of malignant mesothelioma in mice This matters because it tells researchers that human mesothelioma is not driven by one rogue gene but by the loss of several cooperating safeguards. Therapies aimed at restoring one brake alone are unlikely to stop the disease, which is part of why treatment has been so difficult.
Three Cell Types, Three Very Different Behaviors
Not all mesothelioma cells look or behave the same. Pathologists classify them into three histological subtypes, and each carries a different prognosis.
- Epithelioid: The most common form, making up roughly half to two-thirds of cases. These cells retain a cobblestone-like shape reminiscent of normal mesothelial cells and tend to respond better to treatment.
- Sarcomatoid: Spindle-shaped, fibroblast-like cells that grow aggressively and resist chemotherapy. This subtype carries the worst prognosis.
- Biphasic: A mix of epithelioid and sarcomatoid cells within the same tumor, with outcomes that depend on the ratio of the two.
Researchers have now created immortalized cell lines that faithfully mimic each of these three subtypes, from the cobblestone epithelioid to the spindle-shaped sarcomatoid to an intermediate form.9PubMed Central. Three newly established immortalized mesothelial cell lines exhibit morphological phenotypes corresponding to malignant mesothelioma epithelioid, intermediate, and sarcomatoid types, respectively The distinction is not just cosmetic. Sarcomatoid cells arise partly through a process called epithelial-to-mesenchymal transition (EMT), where cells lose their organized, tissue-like character and become more mobile and invasive. Activation of EMT-related signals in mesothelioma is linked to the sarcomatoid form and to shorter survival.10European Journal of Cardio-Thoracic Surgery. Prognostic significance of epithelial–mesenchymal transition in malignant pleural mesothelioma
How Pathologists Tell Mesothelioma Cells Apart from Other Cancers
Under a microscope, mesothelioma can look deceptively similar to lung adenocarcinoma or other cancers that spread to the chest lining. The distinction matters enormously because the treatments are different. Pathologists rely on a panel of protein markers expressed on the cell surface to make the call.
Calretinin, a calcium-binding protein, is one of the most reliable. It shows up in over 90% of epithelioid mesotheliomas but also, confusingly, in a fair share of adenocarcinomas.11PubMed. HBME-1, MOC-31, WT1 and calretinin: an assessment of recently described markers for mesothelioma and adenocarcinoma That is why no single marker is used alone. Combining calretinin with a second marker called D2-40 (podoplanin) pushes sensitivity to 96% for epithelioid areas and about 66% for sarcomatoid areas.12PubMed. D2-40 and calretinin – a tissue microarray analysis of 341 malignant mesotheliomas with emphasis on sarcomatoid differentiation WT1 is another useful marker, positive in roughly 72% of mesotheliomas but only about 20% of adenocarcinomas, while MOC-31 runs the other way: positive in 90% of adenocarcinomas but only 5% of mesotheliomas.13PubMed. HBME-1, MOC-31, WT1 and calretinin: an assessment of recently described markers for mesothelioma and adenocarcinoma By using positive and negative markers in combination, pathologists can usually reach a confident diagnosis. Sarcomatoid tumors remain the trickiest because they lose many of the classic mesothelial markers, which is where the calretinin-plus-D2-40 panel adds the most value.
Mesothelin, a glycoprotein found at low levels in normal tissues but at high levels in mesothelioma, serves double duty: it helps confirm diagnosis and has become a therapeutic target in its own right.14PubMed Central. Hitting the Bull’s-Eye: Mesothelin’s Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma
The Immune Landscape Around Mesothelioma Cells
Mesothelioma tumors do not exist in isolation. They are surrounded by a dense neighborhood of immune cells, blood vessels, and structural tissue collectively known as the tumor microenvironment. A striking feature of this neighborhood is the heavy presence of macrophages, immune cells that in healthy tissue would eat invaders but in the tumor setting often get co-opted to help the cancer grow.
Transcriptomic analysis of the mesothelioma microenvironment has identified at least two distinct macrophage populations contributing to tumor progression. Both promote inflammation and EMT, but they activate different signaling programs.15PubMed Central. Defining and targeting tumor-associated macrophages in malignant mesothelioma In laboratory experiments, when macrophages were co-injected with mesothelioma cells in mice, tumors grew faster. Depleting those macrophages with an antibody caused tumors to shrink, providing direct evidence that macrophages fuel tumor growth rather than fighting it.16PubMed Central. Murine mesothelioma induces locally-proliferating IL-10(+)TNF-α(+)CD206(-)CX3CR1(+) M3 macrophages that can be selectively depleted by chemotherapy or immunotherapy These tumor-trained macrophages still stimulated T cell proliferation but blocked T cells from producing the key anti-tumor protein interferon-gamma, essentially producing an immune response with the teeth removed.
This hostile microenvironment also involves PD-L1, the immune-checkpoint protein that many modern immunotherapies target. Roughly 22 to 27% of mesotheliomas express PD-L1 on tumor cells as measured by FDA-approved companion assays, and PD-L1 levels on tumor cells are strongly correlated with expression on nearby immune cells.17PubMed. Tumor PD-L1 expression in malignant pleural and peritoneal mesothelioma by Dako PD-L1 22C3 pharmDx and Dako PD-L1 28-8 pharmDx assays However, PD-L1 expression is not static. In peritoneal mesothelioma, patients who received chemotherapy before biopsy had lower rates of PD-L1 expression, and when researchers tracked expression over time, roughly 30% of patients saw PD-L1 go up after treatment while 40% saw it go down.18British Journal of Cancer. Heterogeneity in PD-L1 expression in malignant peritoneal mesothelioma with systemic or intraperitoneal chemotherapy That shifting expression matters because it means a biopsy taken at one point may not accurately predict whether checkpoint immunotherapy will work.
Stem-Like Cells and Why Mesothelioma Comes Back
One of the most frustrating aspects of mesothelioma treatment is that even when chemotherapy appears to work initially, the cancer tends to recur. A growing body of evidence points to a small subpopulation of cancer stem cells (CSCs) within the tumor as the source of that recurrence. These cells share characteristics with normal stem cells, including the ability to self-renew and to initiate new tumors from very small numbers.
Researchers have identified mesothelioma CSCs by their expression of specific surface markers. Cells with high levels of a protein called ALDH combined with CD44 showed tolerance to cisplatin, the backbone drug in mesothelioma chemotherapy.19PubMed Central. Cisplatin-resistant cells in malignant pleural mesothelioma cell lines show ALDH(high)CD44(+) phenotype and sphere-forming capacity A separate approach used reporters for the stemness genes OCT4 and SOX2 to isolate a small cell subpopulation that was more resistant to cisplatin, had higher tumor-initiating capacity in mouse models, and was more sensitive to a drug targeting the FAK pathway.20Stem Cell Reports. Identification and Characterization of Mesothelioma Stem-like Cells Driving Recurrence The observation that these stem-like cells are resistant to standard chemotherapy but vulnerable to different drug classes has opened a line of research aimed at combination strategies: kill the bulk tumor with cisplatin, then target the leftover stem-like cells with something else before they can regrow.
Methods for characterizing these cells include sphere-formation assays, where stem-like cells form floating clusters in suspension, and in vivo transplantation, where researchers inject decreasing numbers of cells into mice to see how few are needed to start a new tumor.21PubMed. The application of cancer stem cell model in malignant mesothelioma
Drug Resistance at the Molecular Level
Beyond stem cells, mesothelioma cells develop resistance to chemotherapy through multiple molecular routes. The standard first-line regimen combines cisplatin (a platinum-based drug that damages DNA) with pemetrexed (which disrupts folate metabolism). In cell-line studies, the two drugs generally have synergistic effects, meaning they work better together than the sum of their individual contributions. But resistance develops, and it does not always follow the same path.22PubMed. Interaction and cross-resistance of cisplatin and pemetrexed in malignant pleural mesothelioma cell lines
In cell lines made resistant to pemetrexed, the main target enzyme of that drug, thymidylate synthase, was often found at elevated levels. When researchers profiled a long-term mesothelioma survivor who eventually developed resistance, they found a broad rewiring: DNA damage repair genes were ramped up, telomere-extending machinery was overexpressed, and cell-adhesion genes were turned down, making cells more mobile and aggressive.23PLOS ONE. Molecular Resistance Fingerprint of Pemetrexed and Platinum in a Long-Term Survivor of Mesothelioma This multi-pronged rewiring helps explain why single-agent salvage therapies so rarely work: the resistant cell has not flipped one switch but remodeled its entire survival strategy.
A Metabolic Weak Spot
Not all mesothelioma cells can make their own supply of the amino acid arginine. Roughly half of patients in one screening study had tumors that lacked the enzyme argininosuccinate synthetase 1 (ASS1), leaving those cells dependent on external arginine to survive.24The Lancet Oncology. Arginine deprivation therapy improves progression-free survival in patients with argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma In a phase 2 trial, depleting arginine with a pegylated enzyme (ADI-PEG20) extended median progression-free survival to about 3.2 months compared with 2 months for supportive care alone. The improvement is modest, but the concept is powerful: instead of trying to poison a cell’s DNA, you starve it of something it cannot manufacture for itself.
One complication, though, is that macrophages in the tumor microenvironment may partially rescue the cancer cells from arginine starvation, providing a form of metabolic resistance mediated by immune-cell interactions under cytokine control.25PubMed Central. A role for macrophages under cytokine control in mediating resistance to ADI-PEG20 (pegargiminase) in ASS1-deficient mesothelioma This is a recurring theme in mesothelioma biology: the microenvironment doesn’t just passively house the tumor but actively protects it.
Engineering the Immune System Against Mesothelin
The high levels of mesothelin on mesothelioma cells have made it a natural target for engineered immune therapies. CAR T-cell therapy involves taking a patient’s own T cells, equipping them with a synthetic receptor that recognizes mesothelin on the tumor surface, and infusing them back into the body. Early clinical trials using anti-mesothelin CAR T cells in mesothelioma have shown the approach is relatively safe, an important first hurdle since some CAR T therapies in other cancers have caused severe inflammatory reactions.26PubMed Central. Anti-Mesothelin CAR T cell therapy for malignant mesothelioma Mesothelin is an attractive target because it is abundant on the diseased tissue and largely absent from healthy tissue, reducing the risk of off-target damage.
However, efficacy remains a challenge. The dense, immunosuppressive microenvironment described earlier can exhaust or deactivate the infused T cells before they finish the job. Ongoing research is exploring ways to armor CAR T cells against this suppression or combine them with checkpoint inhibitors to keep the engineered cells active longer within the tumor.27PubMed Central. CAR T-cell therapy for pleural mesothelioma: Rationale, preclinical development, and clinical trials
Epigenetic Silencing and MicroRNA
Beyond outright mutations, mesothelioma cells also suppress genes through epigenetic mechanisms, particularly by methylating gene promoters so they can no longer be read. One example is the microRNA miR-137, whose expression varies widely among mesothelioma cell lines and patient tissue. That variation tracks with both changes in copy number and promoter hypermethylation.28PubMed. Dysregulated Expression of the MicroRNA miR-137 and Its Target YBX1 Contribute to the Invasive Characteristics of Malignant Pleural Mesothelioma When miR-137 is silenced, its target gene YBX1 is left unchecked, contributing to the invasive behavior of the tumor. Findings like these suggest that some of mesothelioma’s aggression is not hardwired into the DNA sequence itself but layered on top through chemical modifications that could, in principle, be reversed with the right drug.
Better Lab Models for Studying These Cells
Much of what we know about mesothelioma cells comes from growing them on flat plastic dishes, but that two-dimensional setup strips away the three-dimensional architecture and cell-to-cell connections that real tumors depend on. Researchers are increasingly turning to 3D culture systems to close this gap.
When mesothelioma cells are grown as spheroids, they form tightly interconnected clusters with cell junctions and surface features like microvilli that are absent in flat culture. Critically, these 3D spheroids are more resistant to chemotherapy drugs than the same cells grown in 2D, more closely resembling what clinicians see in patients.29PubMed Central. 3-Dimensional mesothelioma spheroids provide closer to natural pathophysiological tumor microenvironment for drug response studies A step beyond spheroids, patient-derived organoids grown in a gel matrix can reproduce the original tumor’s tissue architecture and maintain its histological features after being transplanted into mice.30PubMed Central. Matrigel-based organoid culture of malignant mesothelioma reproduces cisplatin sensitivity through CTR1 These organoids retain key mesothelioma biomarkers like calretinin and thrombomodulin, allowing drug screens to be run on tissue that behaves more like the patient’s actual tumor. The hope is that testing therapies in these more realistic models before moving to clinical trials will weed out drugs that look promising on a flat dish but fail in the body.
Tumor Treating Fields
An unconventional approach being investigated for mesothelioma involves tumor treating fields (TTFields), which use alternating electric fields applied externally to disrupt cell division. When epithelioid mesothelioma cells were exposed to TTFields in the lab, they accumulated in the G2/M phase of the cell cycle, failed to complete division, and became polyploid. Apoptosis appeared early in epithelioid cells but only at later time points in sarcomatoid cells, underscoring again how much the histological subtype shapes treatment response.31Cell Death & Disease. Tumor treating fields affect mesothelioma cell proliferation by exerting histotype-dependent cell cycle checkpoint activations and transcriptional modulations
TTFields may also enhance chemotherapy. In preclinical models, applying the fields increased DNA double-strand breaks and suppressed the Fanconi Anemia–BRCA DNA repair pathway, which cells normally use to fix the kind of damage that platinum drugs cause.32PubMed. Tumor Treating Fields (TTFields) downregulate the Fanconi Anemia-BRCA pathway and increase the efficacy of chemotherapy in malignant pleural mesothelioma preclinical models If that finding translates to patients, combining TTFields with cisplatin-based chemotherapy could be a way to chip away at the resistance problem by disabling one of the cancer cell’s key repair mechanisms at the same time the drug is inflicting damage.