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Professor Thomas Seyfried and the question as to whether cancer is primarily nucDNA or mtDNA

Professor Thomas Seyfried and the Question: Is Cancer Primarily Nuclear DNA or Mitochondrial DNA?

Professor Thomas Seyfried argues that cancer is mainly mitochondrial rather than purely nuclear/genetic. Below are the key experiments supporting the view that cytoplasmic/mitochondrial factors, rather than nuclear mutations alone, drive the malignant phenotype.

Nuclear Transfer Experiments (Cancer Nuclei → Normal Cytoplasm)

  1. McKinnell, R.G., Deggins, B.A., Labat, D.D. (1969)
    Transplantation of pluripotential nuclei from triploid frog tumors
    Science, 165(3891):394-6

    Summary: Nuclei from frog renal tumor cells transplanted into enucleated eggs developed into normal swimming tadpoles, demonstrating that cancer nuclei retained developmental pluripotency when placed in normal cytoplasm.

  2. McKinnell, R.G. (1979)
    The pluripotential genome of the frog renal tumor cell as revealed by nuclear transplantation
    International Review of Cytology Supplement, 9:179-88

    Summary: Comprehensive review demonstrating that frog renal adenocarcinoma nuclei could support complete embryonic development.

  3. Mintz, B., Illmensee, K. (1975)
    Normal genetically mosaic mice produced from malignant teratocarcinoma cells
    PNAS, 72(9):3585-9

    Summary: Malignant teratocarcinoma cells (maintained as tumor for 8 years through 200+ transplant generations) injected into blastocysts produced normal mosaic mice. Tumor-derived cells contributed to many normal tissues and even formed functional sperm.

  4. Illmensee, K., Mintz, B. (1976)
    Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts
    PNAS, 73(2):549-53

    Summary: Single malignant teratocarcinoma cells contributed substantially to all somatic tissues in adult mosaic mice. All mosaic mice remained free of teratomas, showing normal embryonic environment could terminate malignant proliferation.

  5. Li, L., et al. (2003)
    Mouse embryos cloned from brain tumors
    Cancer Research, 63(11):2733-42

    Summary: Nuclei from mouse medulloblastomas transferred into enucleated oocytes formed embryos with normal early development. Recipients did not develop tumors, showing tumor nuclei can be normalized by oocyte cytoplasm.

  6. Hochedlinger, K., et al. (2004)
    Reprogramming of a melanoma genome by nuclear transplantation
    Genes & Development, 18(15):1875-85

    Summary: Melanoma and p53⁻/⁻ tumor nuclei transplanted into oocytes yielded blastocysts and ES cells with regulated growth. Despite chromosomal abnormalities, the malignant phenotype was largely erased by oocyte cytoplasm.

Cytoplasmic Transfer Experiments (Normal Nuclei → Cancer Cytoplasm)

  1. Israel, B.A., Schaeffer, W.I. (1987)
    Cytoplasmic suppression of malignancy
    In Vitro Cellular & Developmental Biology, 23(9):627-32

    Summary: Cybrid cells with tumor nuclei but normal cytoplasm showed markedly reduced malignancy, suggesting cytoplasmic factors can override nuclear oncogenic mutations.

  2. Israel, B.A., Schaeffer, W.I. (1988)
    Cytoplasmic mediation of malignancy
    In Vitro Cellular & Developmental Biology, 24(5):487-90

    Summary: When normal nuclei were fused with malignant cytoplasm, 97% produced tumors. When whole normal cells were fused with malignant cytoplasts, only 17% produced tumors. This demonstrated cytoplasm is the primary mediator of malignancy.

  3. Koura, M., et al. (1982)
    Suppression of tumorigenicity in interspecific reconstituted cells and cybrids
    Gan, 73(4):574–80

    Summary: Tumor cell nuclei combined with cytoplasm from non-malignant cells lost their ability to form tumors, showing normal cytoplasm can suppress malignant nuclear genomes.

  4. Shay, J.W., Werbin, H. (1988)
    Cytoplasmic suppression of tumorigenicity in reconstructed mouse cells
    Cancer Research, 48(4):830–833

    Summary: Mouse karyoplast/cytoplast reconstructions demonstrated normal cytoplasm can suppress tumor-forming ability of cancer cell nuclei.

  5. Shay, J.W., et al. (1988)
    Cytoplasmic suppression of tumor progression in reconstituted cells
    Somatic Cell and Molecular Genetics, 14(6):345–350

    Summary: Cytoplasmic composition affects not only initial tumorigenicity but can also slow or inhibit progression of malignancy in reconstituted cells.

Cell Fusion Studies (Tumor × Normal Cell Hybrids)

  1. Harris, H., Bregula, U., Klein, G. (1971)
    The analysis of malignancy by cell fusion. II. Hybrids between Ehrlich cells and normal diploid cells
    Journal of Cell Science, 8(3):673-80

    Summary: Fusion of malignant Ehrlich tumor cells with normal fibroblasts resulted in hybrids showing suppression of malignancy, indicating normal cells contain factors that override the cancer phenotype.

  2. Klein, G., Friberg, S., Harris, H. (1972)
    Two kinds of antigen suppression in tumor cells revealed by cell fusion
    Journal of Experimental Medicine, 135(4):839-49

    Summary: When TA3/Ha cells (with reduced H-2 antigens) were fused with normal fibroblasts, full antigen expression was restored, demonstrating antigen suppression behaved as a recessive, reversible character.

  3. Klein, G., Friberg, S., Wiener, F., Harris, H. (1973)
    Hybrid cells derived from fusion of TA3-Ha ascites carcinoma with normal fibroblasts
    Journal of the National Cancer Institute, 50(5):1259-68

    Summary: Further characterization of tumor-normal hybrids showing reduced malignancy and restoration of normal antigenic properties.

  4. Jonasson, J., Harris, H. (1977)
    The analysis of malignancy by cell fusion VIII: evidence for the intervention of an extra-chromosomal element
    Journal of Cell Science, 24(1):255-63

    Summary: Human diploid cells fused with mouse melanoma cells showed malignancy could be suppressed even when most human chromosomes were lost, suggesting an extra-chromosomal (cytoplasmic) factor influences malignancy.

  5. Howell, N., Sager, R. (1978)
    Tumorigenicity and its suppression in cybrids of mouse and Chinese hamster cell lines
    PNAS, 75(5):2358-62

    Summary: Mouse/hamster cybrids combining tumor nuclei with normal cytoplasm frequently lost tumorigenicity, whereas reverse combinations remained malignant, implicating cytoplasmic/mitochondrial determinants.

  6. Harris, A., Harris, H., Hollingsworth, M.A. (2007)
    Complete suppression of tumor formation by high levels of basement membrane collagen
    Molecular Cancer Research, 5(12):1241-5

    Summary: Highly malignant cervical carcinoma cells transfected with collagen XV showed dose-dependent complete suppression of tumor formation at high expression levels, demonstrating environmental/extracellular factors can override malignant behavior.

Mitochondrial DNA Studies

  1. Petros, J.A., et al. (2005)
    mtDNA mutations increase tumorigenicity in prostate cancer
    PNAS, 102(3):719-24

    Summary: Cybrid experiments exchanging mitochondrial DNA showed cancer-associated mtDNA mutations increase ROS and markedly enhance tumor growth, directly linking mitochondrial genotype to tumor aggressiveness.

  2. Kaipparettu, B.A., et al. (2013)
    Crosstalk from non-cancerous mitochondria can inhibit tumor properties of metastatic cells
    PLoS One, 8(5):e61747

    Summary: Introducing non-cancerous mitochondria into metastatic cancer cells reduced proliferation, migration and tumor formation, and down-regulated oncogenic signaling, highlighting mitochondria as active regulators of the malignant phenotype.

Key Review Paper



The URLs
https://doi.org/10.1126/science.165.3891.394
https://doi.org/10.1016/s0074-7696(08)60903-1
https://doi.org/10.1073/pnas.72.9.3585
https://doi.org/10.1073/pnas.73.2.549
https://aacrjournals.org/cancerres/article/63/11/2733/510012/Mouse-Embryos-Cloned-from-Brain-Tumors
https://genesdev.cshlp.org/content/18/15/1875.long
https://pubmed.ncbi.nlm.nih.gov/3654482/
https://pubmed.ncbi.nlm.nih.gov/7152196/
https://pubmed.ncbi.nlm.nih.gov/3123054/
https://link.springer.com/article/10.1007/BF01534642
https://doi.org/10.1242/jcs.8.3.673
https://doi.org/10.1084/jem.135.4.839
https://doi.org/10.1093/jnci/50.5.1259
https://journals.biologists.com/jcs/article/24/1/255/58422/
https://doi.org/10.1073/pnas.75.5.2358
https://doi.org/10.1073/pnas.0408894102
https://doi.org/10.1371/journal.pone.0061747
https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2015.00043/full

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