bioRxiv Science⌕ Search

bioRxiv · 10.1101/787853

Electron Microscopic Identification of Distant Metastatic Cell in Human Prostate Cancer in Tissue section

Abstract

Mutation in chromatin/DNA/genes of stem cells is a prerequisite for the development of cancer in the benign prostate. Mutation imparts chronic proliferation advantage to invasive and metastatic cancer cells, but not in benign prostate. We hypothesize that identification of metastatic prostatic cancer (PC) cells in tissue sections can lead to an early diagnosis and treatment of patients, hopefully, reducing death due to this disease. We have tested our hypothesis using biopsy and/or radical prostatectomy specimens of untreated and DES (diethylstilbestrol)-treated prostate cancer and transmission electron microscopy. Materials and methods: Tissue samples embedded in Epon were thin sectioned and examined on RCA EMU 3 or 4 transmission electron microscope. Results: We have identified two types of PC stem cells. Invasive stem cell invades the adjacent stroma whereas metastatic cell, a lineage of stem cell, is dedifferentiated columnar/cuboidal cells. Metastatic cell is identified by nuclear plasticity (pleomorphic nucleus), loss of nuclear membranes, loss of boundary between nucleus and cytoplasm and presence of electron dense molecules. Nuclear chromatin/DNA appears as electron dense molecules which readily pass plasma and basement membranes and enter the capillary before adhering to the red cell surface. Electron dense molecules are found in capillary, undoubtedly, reach metastatic site (s). Discussion and conclusion: Chromatin/DNA are small molecules that can readily cross many barriers, unlike an individual cancer cell. We show that invasive a cell is stem cell and metastasis develops from dedifferentiated columnar/cuboidal nuclear electron dense molecules. This is the first study to cells characterize metastatic cell in tissue sections.

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Sinha, A. A.. 2019-09-30. Electron Microscopic Identification of Distant Metastatic Cell in Human Prostate Cancer in Tissue section. https://doi.org/10.1101/787853

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

Tet2-Clonal Hematopoiesis Promotes Whereas Dnmt3a-CH Inhibits Breast Cancer Progression During Aging

Clonal hematopoiesis of indeterminate potential (CHIP) driven by somatic mutations in blood cells increases with age and is associated with adverse outcomes in cancer patients. How CHIP mutations influence solid tumor progression remains unclear. Using inducible murine models of Dnmt3a- or Tet2-mutant CHIP combined with orthotopic syngeneic breast cancer models, we demonstrate that upon aging Dnmt3a-mutant CHIP prevents whereas Tet2-mutant CHIP drives breast cancer progression. Dnmt3a-mutant immune infiltrates established interferon-mediated MHCIIhigh tumor-associated macrophages (TAMs) that supported cytotoxic CD8+ T cell-mediated tumor rejection. In contrast, Tet2-mutant TAMs exhibited an inflammatory, immunosuppressive phenotype characterized by increased IL-1 and CXCL2 production, reduced MHCII expression, and impaired T cell recruitment and activation. Therapeutic blockade of IL-1R1 or CXCR2 reduced tumor progression in aged Tet2-mutant CHIP mice and partially restored anti-tumor immunity. These findings establish that the effects of CHIP on cancer are mutation- and age-dependent and identify IL-1/CXCL2-driven inflammation as a therapeutic vulnerability of tumor-promoting Tet2-mutant CHIP.

cancer biology↗

Single Nucleus Profiling Reveals Rewired Tumor-Immune-Stromal Cell Communication in Plasmacytoid Urothelial Carcinoma

Plasmacytoid urothelial carcinoma (PUC) is an aggressive histologic subtype of bladder cancer associated with worse patient outcomes and therapeutic response compared to conventional urothelial carcinoma (CUC). While recent work has demonstrated metastatic lymph nodes from PUC tumors have an inflamed phenotype, how the tumor microenvironment (TME) and crosstalk between tumor, stromal, and immune cells in primary PUC bladder tumors differs from those in CUC remains poorly understood. The impact of these differences on response to immunotherapy is also unknown. To understand TME differences between CUC and PUC and their impact on cell signaling, we performed single nucleus RNA sequencing on PUC and CUC tumors, as well as Xenium spatial transcriptomics on a mixed CUC / PUC tumor. We identified increased signaling between PUC-enriched, CDH1-low urothelial cells, immunosuppressive lipid-associated macrophages, and SFRP2+/CTHRC1+ fibroblasts in PUC tumors compared to CUC. Spatial transcriptomics identified increased macrophage infiltration in PUC histology and colocalization of PUC tumor cells, immunosuppressive macrophages, and SFRP2+ fibroblasts. Taken together, this study delineates PUC architecture and demonstrates interplay CDH1-low tumor cells, EMT, and immunosuppressive macrophages, identifying possible therapeutic vulnerabilities in PUC.

cancer biology↗

The Phospholipase A2 Activity of Peroxiredoxin 6 Protects Hepatocarcinoma Cells Against Ferroptosis and Mitophagy Impairment

Peroxiredoxin 6 (PRDX6) is a moonlighting protein that plays a key role in regulating redox homeostasis and lipid metabolism through its unique dual peroxidase and calcium-independent phospholipase A2 (iPLA2) activities. Here, we generated a stable HepG2 cell line harboring a D140A mutation to selectively ablate iPLA2 activity, and we compared its phenotype with that of wild-type (WT) and PRDX6-knockout (KO) cells. D140A exhibited low ROS leves, similar to WT cells, confirming that oxidative stress is due to peroxidase deficiency. In contrast, D140A cells displayed higher lipid peroxidation than WT cells, though significantly lower than that of KO cells. Furthermore, the D140A mutant mirrored the KO phenotype regarding intracellular ferrous iron accumulation, impaired lipid droplet biogenesis, and the downregulation of the key ferroptosis regulator GPX4. Mechanistically, integrated proteomic, lipidomic, and enzymatic analyses revealed that a deficiency in iPLA2 activity of PRDX6 disrupted the release of key lipid species necessary for cell structure and signaling. Consequently, organelles involved in lipid synthesis and trafficking, such as peroxisomes, endoplasmic reticulum, mitochondria and lipid droplet, were affected. Specifically, we found that mitochondria exhibited a reduction in cristae and a diminished capacity for mitophagy and autophagy, which ultimately makes cells much more susceptible to erastin-induced ferroptotic cell death. Taken together, our findings demonstrate that PRDX6 iPLA2 activity uniquely coordinates organelle lipid homeostasis and mitophagy to protect cancer cells from ferroptotic cell death. Consequently, the use of iPLA2 inhibitors such as MJ33, which decreased PRDX6 iPLA2 activity to a level comparable to the mutant D140A, could represent a promising therapeutic strategy for inducing ferroptotic cell death in hepatocellular carcinoma.

cancer biology↗