Observational study finds mesothelial cells influence ovarian cancer cell behavior — Evidence Review
Published in Science Advances, by researchers from Nagoya University
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Table of Contents
Ovarian cancer spreads quickly by co-opting mesothelial cells, forming hybrid cell clusters that carve invasion pathways and resist chemotherapy, according to new research from Nagoya University. Related studies largely support these findings, showing that mesothelial cells are active contributors to ovarian cancer metastasis and therapy resistance.
- Multiple studies demonstrate that mesothelial cells, once thought to be passive barriers, are actively manipulated by ovarian cancer cells to enhance invasion, metastasis, and chemoresistance, often through signaling pathways such as TGF-β1 and secreted factors like fibronectin or osteopontin 1 3.
- The concept of cancer cells recruiting and modifying local stromal or immune cells to assist in tissue invasion and metastasis is supported in ovarian and other cancers, with mechanisms involving exosomes, cell adhesion molecules, and the induction of mesenchymal phenotypes in recruited cells 2 4.
- The new study's focus on the formation of chemoresistant hybrid cell spheres in abdominal fluid expands upon earlier work that identified the tumor-promoting role of the ovarian cancer microenvironment and suggests novel targets for therapy and disease monitoring 3 12 13.
Study Overview and Key Findings
Ovarian cancer remains the deadliest gynecological malignancy, in large part due to its late detection and rapid, diffuse spread within the abdominal cavity. Unlike most cancers that metastasize through blood vessels, ovarian cancer cells disseminate via the peritoneal fluid, making their movements difficult to track or intercept. This study addresses a longstanding gap in understanding how ovarian cancer cells traverse and invade abdominal tissues so efficiently, revealing that these cells recruit mesothelial cells to pioneer pathways for invasion and to form compact, drug-resistant clusters.
| Property | Value |
|---|---|
| Organization | Nagoya University |
| Journal Name | Science Advances |
| Authors | Dr. Kaname Uno |
| Population | Patients with ovarian cancer |
| Methods | Observational Study |
| Outcome | Cancer cell behavior and hybrid cell cluster formation |
| Results | About 60% of cancer spheres contain recruited mesothelial cells. |
Literature Review: Related Studies
To place these findings into context, we searched the Consensus database of over 200 million research papers using the following queries:
- ovarian cancer mesothelial cells interaction
- cancer spheres cell recruitment mechanisms
- tumor microenvironment ovarian cancer outcomes
Literature Review Table
| Topic | Key Findings |
|---|---|
| How do mesothelial cells contribute to ovarian cancer metastasis? | - Mesothelial cells are activated by cancer cells (via TGF-β1) to secrete fibronectin and adopt a mesenchymal phenotype, promoting early metastasis 1. - Cancer exosomes cause mesothelial cells to express CD44 and facilitate invasion 2. |
| What mechanisms underlie chemoresistance in ovarian cancer spheres? | - Mesothelial-derived osteopontin, induced by TGF-β signaling from cancer cells, enhances chemoresistance and stemness 3. - Hybrid cell clusters in the peritoneal cavity are more resistant to therapy than cancer cells alone 3. |
| How does the tumor microenvironment shape ovarian cancer progression? | - The ovarian cancer microenvironment, including mesothelial and immune cells, supports tumor growth, immune evasion, and therapy resistance 4 12 13 14. - Interactions with macrophages and other stromal cells affect metastasis 5 15. |
| What is the role of TGF-β signaling and cell-cell communication? | - Ovarian cancer cells use TGF-β1 to manipulate mesothelial cells, leading to invasion and metastatic niche formation 1 3. - Exosome-mediated transfer of proteins like CD44 further enhances invasiveness 2. |
How do mesothelial cells contribute to ovarian cancer metastasis?
The new study builds upon a growing body of evidence showing that mesothelial cells are not passive barriers but are instead co-opted by ovarian cancer cells to facilitate metastasis. Previous research has shown that mesothelial cells, when activated by TGF-β1 from cancer cells, secrete fibronectin and undergo mesenchymal transition, aiding tumor cell adhesion and invasion 1. Similarly, exosome-mediated transfer of CD44 and other molecules to mesothelial cells increases their ability to promote cancer cell invasion 2.
- Mesothelial cells can be reprogrammed by ovarian cancer cells to support metastatic colonization via secretion of extracellular matrix proteins like fibronectin 1.
- Cancer-derived exosomes induce mesothelial cells to express molecules (e.g., CD44) that promote cancer cell adhesion and invasion 2.
- The new study’s observation that about 60% of cancer spheres in ascites fluid contain mesothelial cells highlights the prevalence of these hybrid clusters in vivo.
- These findings collectively suggest that disrupting the communication between cancer cells and mesothelial cells could be a therapeutic strategy 1 2.
What mechanisms underlie chemoresistance in ovarian cancer spheres?
Chemoresistance is a major obstacle in treating ovarian cancer. Recent studies, including the new research, indicate that hybrid cell clusters comprising both cancer and mesothelial cells exhibit enhanced resistance to chemotherapy 3. Osteopontin, secreted by cancer-associated mesothelial cells in response to TGF-β signaling, has been identified as a mediator of this chemoresistance and may contribute to maintaining cancer stemness 3.
- Hybrid spheres formed by cancer and mesothelial cells are more resistant to chemotherapy than cancer cells alone 3.
- Osteopontin signaling from mesothelial cells, induced by TGF-β, promotes chemoresistance and is associated with poor prognosis 3.
- Blocking osteopontin or the TGF-β pathway improves responses to platinum chemotherapy in preclinical models 3.
- The formation of multicellular spheres and their stem-like characteristics are a key mechanism for therapy evasion in ovarian cancer 3 6 7 10.
How does the tumor microenvironment shape ovarian cancer progression?
The ovarian cancer tumor microenvironment (TME) is a complex milieu of cancer cells, mesothelial cells, immune cells, and soluble factors. This environment not only supports tumor growth and dissemination but also impairs immune responses and mediates resistance to therapy 4 12 13 14. The peritoneal fluid, in particular, provides a unique route for cancer cell spread and houses numerous cell types that interact with the tumor.
- The ovarian cancer TME is enriched with mesothelial cells, immune cells (macrophages, T cells), and extracellular vesicles that collectively create a tumor-promoting environment 4 12 13.
- The peritoneal cavity’s fluid dynamics enable widespread cancer dissemination, distinct from hematogenous metastasis 4.
- Immune and stromal cells in the TME contribute to immune evasion and therapy resistance 12 14 15.
- The new study’s identification of mesothelial-cancer cell clusters as key players in invasion and resistance further underscores the importance of TME interactions 4 12 13.
What is the role of TGF-β signaling and cell-cell communication?
TGF-β signaling acts as a central mediator in the dialog between ovarian cancer cells and mesothelial cells, as established by several studies 1 3. By releasing TGF-β1, cancer cells induce mesothelial cells to take on invasive characteristics, such as producing invadopodia or secreting pro-metastatic factors. Exosome-mediated transfer of proteins (such as CD44) also plays a role in modifying mesothelial cell behavior and enhancing invasion 2.
- TGF-β1 released by cancer cells activates mesothelial cells, leading them to promote invasion and chemoresistance 1 3.
- Exosome-mediated cell-cell communication transfers invasion-promoting molecules to mesothelial cells 2.
- TGF-β signaling is implicated in both metastasis and the maintenance of stem-like/chemoresistant properties in cancer cell spheres 1 3 6.
- Targeting TGF-β or exosome-mediated pathways may disrupt these pro-tumorigenic interactions 1 2 3.
Future Research Questions
While substantial progress has been made in understanding ovarian cancer metastasis and chemoresistance, important questions remain. Further research is needed to clarify the molecular details of cancer-mesothelial cell interactions, explore potential therapeutic targets, and develop better diagnostic and monitoring tools.
| Research Question | Relevance |
|---|---|
| Can blocking TGF-β1 signaling prevent the formation of hybrid cell clusters and reduce ovarian cancer metastasis? | TGF-β1 is central to the recruitment and activation of mesothelial cells in promoting metastasis; targeting this pathway may offer a novel therapeutic approach 1 3. |
| How do hybrid cancer-mesothelial spheres evade chemotherapy at the molecular level? | Understanding the molecular mechanisms of chemoresistance in these hybrid clusters could identify new drug targets and improve treatment outcomes 3 10. |
| Can monitoring hybrid cell clusters in abdominal fluid improve early detection or predict treatment response in ovarian cancer? | The presence and abundance of these clusters could serve as a biomarker for disease progression or therapy efficacy, addressing the current gap in early detection 4 12 13. |
| What other cell types in the tumor microenvironment cooperate with mesothelial cells to promote ovarian cancer? | Ovarian cancer progression is influenced by a network of stromal and immune cells; identifying their roles could reveal additional therapeutic targets 4 5 12 14 15. |
| Are exosome-mediated communications between cancer and mesothelial cells essential for metastasis, and can they be therapeutically targeted? | Exosomes play a role in altering mesothelial cell behavior to favor invasion; targeting exosome production or uptake may offer new treatment avenues 2. |