The malignant pleural effusion as a model to investigate intratumoral heterogeneity in lung cancer.
Malignant Pleural Effusions (MPE) may be useful as a model to study hierarchical progression of cancer and/or intratumoral heterogeneity. To strengthen the rationale for developing the MPE-model for these purposes, we set out to find evidence for the presence of cancer stem cells (CSC) in MPE and demonstrate an ability to sustain intratumoral heterogeneity in MPE-primary cultures. Our studies show that candidate lung CSC-expression signatures (PTEN, OCT4, hTERT, Bmi1, EZH2 and SUZ12) are evident in cell pellets isolated from MPE, and MPE-cytopathology also labels candidate-CSC (CD44, cMET, MDR-1, ALDH) subpopulations. Moreover, in primary cultures that use MPE as the source of both tumor cells and the tumor microenvironment (TME), candidate CSC are maintained over time. This allows us to live-sort candidate CSC-fractions from the MPE-tumor mix on the basis of surface markers (CD44, c-MET, uPAR, MDR-1) or differences in xenobiotic metabolism (ALDH). Thus, MPE-primary cultures provide an avenue to extract candidate CSC populations from individual (isogenic) MPE-tumors. This will allow us to test whether these cells can be discriminated in functional bioassays. Tumor heterogeneity in MPE-primary cultures is evidenced by variable immunolabeling, differences in colony-morphology, and differences in proliferation rates of cell subpopulations. Collectively, these data justify the ongoing development of the MPE-model for the investigation of intratumoral heterogeneity, tumor-TME interactions, and phenotypic validation of candidate lung CSC, in addition to providing direction for the pre-clinical development of rational therapeutics.
Basak
Saroj K
SK
Wadsworth Stem Cell Institute, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, United States of America.
Veena
Mysore S
MS
Oh
Scott
S
Huang
Ge
G
Srivatsan
Eri
E
Huang
Min
M
Sharma
Sherven
S
Batra
Raj K
RK
D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D045744:Cell Line, Tumor; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000473:pathology*; D008297:Male; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010641:Phenotype; D016066:Pleural Effusion, Malignant / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking / Q000009:adverse effects; D013234:Stem Cells / Q000166:cytology
D000444:Aldehyde Dehydrogenase