Tackling tumor heterogeneity and phenotypic plasticity in cancer precision medicine: our experience and a literature review.
The predominant cause of cancer mortality is metastasis. The major impediment to cancer cure is the intrinsic or acquired resistance to currently available therapies. Cancer is heterogeneous at the genetic, epigenetic, and metabolic levels. And, while a molecular-targeted drug may be pathway-precise, it can still fail to achieve wholesome cancer-precise toxicity. In the current review, we discuss the strategic differences between targeting the strengths of cancer cells in phenotypic plasticity and heterogeneity and targeting shared vulnerabilities of cancer cells such as the compromised integrity of membranous organelles. To better recapitulate subpopulations of cancer cells in different phenotypic and functional states, we developed a schematic combination of 2-dimensional culture (2D), 3-dimmensional culture in collagen I (3D), and mammosphere culture for stem cells (mammosphere), designated as Scheme 2D/3D/mammosphere. We investigated how the tumor suppressor maspin may limit carcinoma cell plasticity and affect their context-dependent response to drugs of different mechanisms including docetaxel, histone deacetylase (HDAC) inhibitor MS-275, and ionophore antibiotic salinomycin. We showed that tumor cell phenotypic plasticity is not an exclusive attribute to cancer stem cells. Nonetheless, three subpopulations of prostate cancer cells, enriched through Scheme 2D/3D/mammosphere, show qualitatively different drug responses. Interestingly, salinomycin was the only drug that effectively killed all three cancer cell subpopulations, irrespective of their capacity of stemness. Further, Scheme 2D/3D/mammosphere may be a useful model to accelerate the screening for curative cancer drugs while avoiding costly characterization of compounds that may have only selective toxicity to some, but not all, cancer cell subpopulations.
['Sheng|Shijie|S|', 'Margarida Bernardo|M|M|', 'Dzinic|Sijana H|SH|', 'Chen|Kang|K|', 'Heath|Elisabeth I|EI|', 'Sakr|Wael A|WA|']
D000222:Adaptation, Physiological D000818:Animals D019008:Drug Resistance, Neoplasm D004354:Drug Screening Assays, Antitumor D006801:Humans D009362:Neoplasm Metastasis D009369:Neoplasms D057285:Precision Medicine
Heterogeneity Scheme 2D/3D/mammosphere Maspin Docetaxel MS-275 Salinomycin Cancer stem cells Cancer strength Cancer vulnerability Cell death Cell survival Drug resistance Drug screening strategy Epithelial-to-mesenchymal transition (EMT) Integrity of membranous subcellular structures Proliferation Transient quiescence