Cancer cells arise from bacteria

It is believed that cancer cells (PCCs) are altered normal cells formed by cell transformation. Based on this belief, extensive studies have been conducted, while the pathogenetic mechanism of cancer is, still, unclear [1]. Hence, this fundamental belief may be questionable. In the following sections, we (1) analyze the cellular processes of cancer cell formation described in the previous researches, (2) compare the similarities between cancer cell formation and cyanobacterium TDX16’s development and transition [2, 3], and (3) propose BOCC hypothesis.

Cancer cell formation is a complex event that can hardly be made clear in vivo. Since the landmark experiments showing that the normal cells in cultures gradually transformed into cancer cells [4, 5], in vitro cell transformation become the model experiment method to mimic in vivo cancer cell formation. The following studies manifested that in vitro cell transformation can occur spontaneously [6‐9] or in the presence of physical stimuli [10], chemical carcinogens [11, 12] and viruses [13‐17] in a similar pattern: the normal cells either completely failed to grow or divided for limited number of generations owing to the finite proliferative lifespan [18] and then became senescent and entered “crisis” [19], consequently most of the cells died, while only rare cells occasionally “escaped” cellular senescence or crisis and survived as the cancer cells, with altered morphology, ultrastructure, chromosomes [6, 20‐22] and growth behavior properties [23, 24].

Nonetheless, the origin and developmental process of cancer cells are unknown, because cell transformations took a long period of time and the obtained cell cultures were composed of a mixture of small undifferentiated cells, polyploidy (hyperchromatic) giant cells (PGCs), flat multinucleated giant cells and sloughing, differentiating cells [7, 14, 15, 25‐27], which made it difficult to track the trajectory of cancer cell development. In this case, cancer cells were postulated to be transformed from the normal cells, usually called “transformed cells”.

Recent studies revealed that the senescing normal cells turned into mitotically incapacitated PGCs, in which small nascent PCCs were being formed, and when PGCs burst, a large number of small PCCs were released [28‐34]. Hence, PCCs are formed in but not transformed from the senescent normal cells. Similarly, new small nascent SCCs were formed in the senescent polyploid giant cancer cells (PGCCs) [32, 35‐46]. These results demonstrated that PCCs and SCCs formations share a common cellular mechanism.

Nevertheless, the cellular mechanism of how the small active PCCs/SCCs were formed in the senescent unviable PGCs/PGCCs is unclear, and remains a paradox. The common explanation is that small nuclei budded from the large PGCs/PGCCs nuclei, and then became small PCCs/SCCs by re-budding off from PGCs/PGCCs, or via asymmetric cytokinesis of PGCs/PGCCs. However, indeed, nuclear budding and cytokinesis were unachievable in the senescent PGCs/PGCCs, because no energy and membrane sources were available for sustaining such active actions.

Different from the common explanation, one study showed that small SCCs were formed in the nuclei of PGCCs [35]. Similar results were frequently reported in early researches: (1) SCCs-like nuclear inclusions were developed within PGCCs nuclei [47]; and (2) PCCs-like pycnotic cells and nuclear inclusions [48], intranuclear inclusion bodies [27, 49], intranuclear membrane-bound inclusions [23] and “micronuclei” [50] were formed in PGCs nuclei, which increased in number and distributed throughout PGCs after the large nuclei disappeared. As to how the intranuclear PCCs/SCCs were formed, it was speculated that SCCs were probably derived from the ‘coiled bodies’ [35], which were, however, delimited by membranes and thus also SCCs but not the membrane-less coiled bodies [51]. Thus, there must be other precursors from which PCCs/SCCs were formed.

Since the small nascent PCCs/SCCs lack organelles and bear resemblances to the intracellular bacteria [52‐61], it is likely that the small PCCs/SCCs were developed from the bacteria within PGCs/PGCCs. This notion may be intuitively unacceptable, but actually is possible in theory that eukaryotes originate from prokaryotes and supported by our finding that the cyanobacterium TDX16 (prokaryote) turned into a new alga TDX16-DE (eukaryote) [2, 3].

Haematococcus pluvialis is a unicellular green alga, which grows well and synthesizes astaxanthin in the conditions of high irradiance and low temperature [62, 63]. Conversely, when cultivated under the adverse conditions of low irradiance and high temperature, the growth of H. pluvialis was inhibited [64]. Light microscopic observation showed that the enlarged H. pluvialis cells were undergoing senescence with no astaxanthin accumulation but chlorophyll reduction (Fig. 1A) and ultimately necrosis: the bloated senescent cell ruptured and liberated a massive blue spheroid consisting of countless small cyanobacterial cells (TDX16) (Fig. 1B). Transmission electron microscope observation revealed that very small premature TDX16 cells with electron dense dot-like heterogenous globular body (HGB) [3] multiplied by asymmetric division within the senescent/necrotic H. pluvialis cell at the expense of the dissolved organelles and cytoplasm (Fig. 2A), and subsequently enlarged into small thylakoid-less TDX16 filling up the cellular space (Fig. 2B) [64]. The liberated TDX16 was light-sensitive and unstable, which changed slowly, maintained prokaryotic state, and displayed different statuses even in the same sporangium in the dim light (Fig. 2C), but turned readily and quickly into a small green alga (TDX16-DE) by de novo organelle biogenesis as light intensity elevated (Fig. 2D) [2, 3]. TDX16-DE is a new species of green alga, containing only a double-envelope-bounded nucleus, a chloroplast, one or more mitochondria and double-membrane-bounded vacuoles, but no other organelles (Fig. 2D) [3]. Sequencing results of 16S rRNA (GenBank KJ599678.2) and Genome (GenBank NDGV00000000) indicate that TDX16 is a cyanobacterium resembling Chroococcidiopsis thermalis, which had acquired 9,017,401 bp DNAs with 10,301 genes from its host H. pluvialis. Thus, the reason for TDX16-to-TDX16-DE transition is the hybridization of the obtained eukaryotic DNA and TDX16’s prokaryotic ones, and expression of the hybrid genome [3].

TDX16’s transition demonstrates that a prokaryotic cyanobacterium can obtain its senescent algal host’s DNA and develop into a new eukaryotic alga. Since bacteria and cyanobacteria are close relatives sharing similar structures and behaviors, it is possible that some bacteria, like TDX16, are capable of prokaryote-to-eukaryote transition under the similar conditions. If so, the bacteria within normal/cancer cells of multicellular eukaryotes may develop into new single-celled eukaryotes: PCCs/SCCs. Consistent with this notion, PCCs/SCCs formation really share striking similarities with TDX16 development and TDX16-to-TDX16-DE transition (Figs. 1, 2):

Based on the above analyses and comparisons, we propose the bacterial origin of cancer cells (BOCC) that PCCs/SCCs arise from bacteria through 8 steps (Fig. 3):

In the way described above, new SCCs can be developed successively from the same or different species of bacteria, which inevitably result in the increased heterogeneity, genetic instability and endless complexity of cancer cells in vivo and in vitro. Hence, PCCs, SCCs and the subsequent new SCCs look superficially like the putative “cancer stem cells” [68] in cancer progression.

The following BOCC-based predictions can be used for testing the hypothesis: