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Cancer as a mitochondrial metabolic disease.

Seyfried TN - Front Cell Dev Biol (2015)

Bottom Line: This view persists despite the numerous inconsistencies associated with the somatic mutation theory.In contrast to the somatic mutation theory, emerging evidence suggests that cancer is a mitochondrial metabolic disease, according to the original theory of Otto Warburg.The evidence from these experiments is difficult to reconcile with the somatic mutation theory, but is consistent with the notion that cancer is primarily a mitochondrial metabolic disease.

View Article: PubMed Central - PubMed

Affiliation: Biology Department, Boston College Chestnut Hill, MA, USA.

ABSTRACT
Cancer is widely considered a genetic disease involving nuclear mutations in oncogenes and tumor suppressor genes. This view persists despite the numerous inconsistencies associated with the somatic mutation theory. In contrast to the somatic mutation theory, emerging evidence suggests that cancer is a mitochondrial metabolic disease, according to the original theory of Otto Warburg. The findings are reviewed from nuclear cytoplasm transfer experiments that relate to the origin of cancer. The evidence from these experiments is difficult to reconcile with the somatic mutation theory, but is consistent with the notion that cancer is primarily a mitochondrial metabolic disease.

No MeSH data available.


Related in: MedlinePlus

Role of the nucleus and mitochondria in the origin of tumors. Summary of a role of the mitochondria in the origin of tumorigenesis, as we previously described (Seyfried, 2012d; Seyfried et al., 2014). Normal cells are shown in green with nuclear and mitochondrial morphology indicative of normal gene expression and respiration, respectively. Tumor cells are shown in red with abnormal nuclear and mitochondrial morphology indicative of genomic instability and abnormal respiration, respectively. “(1) Normal cells beget normal cells. (2) Tumor cells beget tumor cells. (3) Transfer of a tumor cell nucleus into a normal cytoplasm begets normal cells, despite the presence of the tumor-associated genomic abnormalities. (4) Transfer of a normal cell nucleus into a tumor cell cytoplasm begets dead cells or tumor cells, but not normal cells. The results suggest that nuclear genomic defects alone cannot account for the origin of tumors, and that normal mitochondria can suppress tumorigenesis” (Seyfried, 2012d). Original diagram from Jeffrey Ling and Thomas N. Seyfried, with permission.
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Figure 3: Role of the nucleus and mitochondria in the origin of tumors. Summary of a role of the mitochondria in the origin of tumorigenesis, as we previously described (Seyfried, 2012d; Seyfried et al., 2014). Normal cells are shown in green with nuclear and mitochondrial morphology indicative of normal gene expression and respiration, respectively. Tumor cells are shown in red with abnormal nuclear and mitochondrial morphology indicative of genomic instability and abnormal respiration, respectively. “(1) Normal cells beget normal cells. (2) Tumor cells beget tumor cells. (3) Transfer of a tumor cell nucleus into a normal cytoplasm begets normal cells, despite the presence of the tumor-associated genomic abnormalities. (4) Transfer of a normal cell nucleus into a tumor cell cytoplasm begets dead cells or tumor cells, but not normal cells. The results suggest that nuclear genomic defects alone cannot account for the origin of tumors, and that normal mitochondria can suppress tumorigenesis” (Seyfried, 2012d). Original diagram from Jeffrey Ling and Thomas N. Seyfried, with permission.

Mentions: Although the nuclear-cytoplasmic transfer experiments fail to support the somatic mutation theory, the data from these experiments strongly support the Warburg theory of cancer. Normal mitochondrial function reverses expression and the Warburg effect because this effect is due to insufficient respiration (Burk and Schade, 1956; Kaipparettu et al., 2013; Seyfried et al., 2014). Aerobic fermentation is an effect of insufficient respiration. Statements about a “reverse Warburg effect,” which do not involve restored respiration in the tumor cells, are difficult to reconcile in light of the information presented here (Pavlides et al., 2009; Seyfried, 2012d). Normal mitochondria would enhance respiration thus suppressing oncogene expression and tumorigenicity, whereas mitochondria taken from cancer cells cannot restore respiration or suppress tumorigenicity. According to Warburg's theory, it would be expected that the presence of normal mitochondria in tumor cells would restore the cellular redox state, down regulate the mitochondrial stress response, and ultimately reduce or eliminate the need for fermentation (the Warburg effect) to maintain viability (Seyfried et al., 2014). In rephrasing, normal mitochondrial function maintains the differentiated state thereby suppressing carcinogenesis, whereas dysfunctional mitochondria can enhance cellular dedifferentiation thereby facilitating carcinogenesis (Seyfried, 2012d). Cuezva and Ristow also show that normal mitochondrial respiration suppresses tumorigenesis (Ristow, 2006; Cuezva et al., 2009; Ristow and Cuezva, 2009). Proliferation is the default state of metazoan cells, i.e., the state under which cells are found when they are freed from any active control (Sonnenschein and Soto, 1999). Mitochondria can maintain the differentiated state and quiescence. The loss of mitochondrial function will lead eventually to the default state of unbridled proliferation, i.e., the metabolic phenotype that was present in all cells during the anoxic alpha period of earth's history (Szent-Gyorgyi, 1977; Seyfried, 2012a). Figure 3 summarizes the role of mitochondria in tumorigenesis.


Cancer as a mitochondrial metabolic disease.

Seyfried TN - Front Cell Dev Biol (2015)

Role of the nucleus and mitochondria in the origin of tumors. Summary of a role of the mitochondria in the origin of tumorigenesis, as we previously described (Seyfried, 2012d; Seyfried et al., 2014). Normal cells are shown in green with nuclear and mitochondrial morphology indicative of normal gene expression and respiration, respectively. Tumor cells are shown in red with abnormal nuclear and mitochondrial morphology indicative of genomic instability and abnormal respiration, respectively. “(1) Normal cells beget normal cells. (2) Tumor cells beget tumor cells. (3) Transfer of a tumor cell nucleus into a normal cytoplasm begets normal cells, despite the presence of the tumor-associated genomic abnormalities. (4) Transfer of a normal cell nucleus into a tumor cell cytoplasm begets dead cells or tumor cells, but not normal cells. The results suggest that nuclear genomic defects alone cannot account for the origin of tumors, and that normal mitochondria can suppress tumorigenesis” (Seyfried, 2012d). Original diagram from Jeffrey Ling and Thomas N. Seyfried, with permission.
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Related In: Results  -  Collection

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Figure 3: Role of the nucleus and mitochondria in the origin of tumors. Summary of a role of the mitochondria in the origin of tumorigenesis, as we previously described (Seyfried, 2012d; Seyfried et al., 2014). Normal cells are shown in green with nuclear and mitochondrial morphology indicative of normal gene expression and respiration, respectively. Tumor cells are shown in red with abnormal nuclear and mitochondrial morphology indicative of genomic instability and abnormal respiration, respectively. “(1) Normal cells beget normal cells. (2) Tumor cells beget tumor cells. (3) Transfer of a tumor cell nucleus into a normal cytoplasm begets normal cells, despite the presence of the tumor-associated genomic abnormalities. (4) Transfer of a normal cell nucleus into a tumor cell cytoplasm begets dead cells or tumor cells, but not normal cells. The results suggest that nuclear genomic defects alone cannot account for the origin of tumors, and that normal mitochondria can suppress tumorigenesis” (Seyfried, 2012d). Original diagram from Jeffrey Ling and Thomas N. Seyfried, with permission.
Mentions: Although the nuclear-cytoplasmic transfer experiments fail to support the somatic mutation theory, the data from these experiments strongly support the Warburg theory of cancer. Normal mitochondrial function reverses expression and the Warburg effect because this effect is due to insufficient respiration (Burk and Schade, 1956; Kaipparettu et al., 2013; Seyfried et al., 2014). Aerobic fermentation is an effect of insufficient respiration. Statements about a “reverse Warburg effect,” which do not involve restored respiration in the tumor cells, are difficult to reconcile in light of the information presented here (Pavlides et al., 2009; Seyfried, 2012d). Normal mitochondria would enhance respiration thus suppressing oncogene expression and tumorigenicity, whereas mitochondria taken from cancer cells cannot restore respiration or suppress tumorigenicity. According to Warburg's theory, it would be expected that the presence of normal mitochondria in tumor cells would restore the cellular redox state, down regulate the mitochondrial stress response, and ultimately reduce or eliminate the need for fermentation (the Warburg effect) to maintain viability (Seyfried et al., 2014). In rephrasing, normal mitochondrial function maintains the differentiated state thereby suppressing carcinogenesis, whereas dysfunctional mitochondria can enhance cellular dedifferentiation thereby facilitating carcinogenesis (Seyfried, 2012d). Cuezva and Ristow also show that normal mitochondrial respiration suppresses tumorigenesis (Ristow, 2006; Cuezva et al., 2009; Ristow and Cuezva, 2009). Proliferation is the default state of metazoan cells, i.e., the state under which cells are found when they are freed from any active control (Sonnenschein and Soto, 1999). Mitochondria can maintain the differentiated state and quiescence. The loss of mitochondrial function will lead eventually to the default state of unbridled proliferation, i.e., the metabolic phenotype that was present in all cells during the anoxic alpha period of earth's history (Szent-Gyorgyi, 1977; Seyfried, 2012a). Figure 3 summarizes the role of mitochondria in tumorigenesis.

Bottom Line: This view persists despite the numerous inconsistencies associated with the somatic mutation theory.In contrast to the somatic mutation theory, emerging evidence suggests that cancer is a mitochondrial metabolic disease, according to the original theory of Otto Warburg.The evidence from these experiments is difficult to reconcile with the somatic mutation theory, but is consistent with the notion that cancer is primarily a mitochondrial metabolic disease.

View Article: PubMed Central - PubMed

Affiliation: Biology Department, Boston College Chestnut Hill, MA, USA.

ABSTRACT
Cancer is widely considered a genetic disease involving nuclear mutations in oncogenes and tumor suppressor genes. This view persists despite the numerous inconsistencies associated with the somatic mutation theory. In contrast to the somatic mutation theory, emerging evidence suggests that cancer is a mitochondrial metabolic disease, according to the original theory of Otto Warburg. The findings are reviewed from nuclear cytoplasm transfer experiments that relate to the origin of cancer. The evidence from these experiments is difficult to reconcile with the somatic mutation theory, but is consistent with the notion that cancer is primarily a mitochondrial metabolic disease.

No MeSH data available.


Related in: MedlinePlus