Evaluating the Remote Control of Programmed Cell Death, with or without a Compensatory Cell Proliferation

Abstract

Organisms and their different component levels, whether organelle, cellular or other, come by birth and go by death, and the deaths are often balanced by new births. Evolution on the one hand has built demise program(s) in cells of organisms but on the other hand has established external controls on the program(s). For instance, evolution has established death program(s) in animal cells so that the cells can, when it is needed, commit apoptosis or senescent death (SD) in physiological situations and stress-induced cell death (SICD) in pathological situations. However, these programmed cell deaths are not predominantly regulated by the cells that do the dying but, instead, are controlled externally and remotely by the cells' superior(s), i.e. their host tissue or organ or even the animal's body. Currently, it is still unclear whether a cell has only one death program or has several programs respectively controlling SD, apoptosis and SICD. In animals, apoptosis exterminates, in a physiological manner, healthy but no-longer needed cells to avoid cell redundancy, whereas suicidal SD and SICD, like homicidal necrosis, terminate ill but useful cells, which may be followed by regeneration of the live cells and by scar formation to heal the damaged organ or tissue. Therefore, “who dies” clearly differentiates apoptosis from SD, SICD and necrosis. In animals, apoptosis can occur only in those cell types that retain a lifelong ability of proliferation and never occurs in those cell types that can no longer replicate in adulthood. In cancer cells, SICD is strengthened, apoptosis is dramatically weakened while SD has been lost. Most published studies professed to be about apoptosis are actually about SICD, which has four basic and well-articulated pathways involving caspases or involving pathological alterations in the mitochondria, endoplasmic reticula, or lysosomes.

Evidence for immortality and autonomy in animal cancer models is often not provided, which causes confusion on key issues of cancer biology

“…For renewable cell types, if the cell number is decreased for some reason, the body will trigger cell proliferation to restore the physiological number. Conversely, if the number is higher than normal, as seen in over-regeneration that often happens following a regeneration procedure, the body will goad some of the cells into apoptosis to avoid cell redundancy [296,302,303,[466][467][468][469]. This is because apoptosis evolves as a specific mechanism to eliminate useless, redundant cells from the tissue or organ [302,303,466,468], but not as a demise mechanism triggered by compensatory proliferation as thought by some peers [470][471][472][473].…”

“…hyperplastic, cells, although it usually does mildly because of a slight overproduction of cells. Killing excessive cells via apoptosis can be implemented in an evolutionarily complex animal because all cells have allegiance to the animal's body, as we described before [296,302,303,[466][467][468], or "conform with the law of organisms", as put by Rous in 1941 [58]. This allegiance as the "law of organisms" allows the host's body to require some renewable cells to sacrifice their lives for the body's ultimate interest.…”

“…This allegiance as the "law of organisms" allows the host's body to require some renewable cells to sacrifice their lives for the body's ultimate interest. An instructive example is that white blood cells are often put on the frontier by the host's body to fight against infectious micropathogens and die in the battle, so that the host as a whole can survive [466,474]. However, sometimes some renewable cells, such as select bone marrow cells, epidermal keratinocytes, and mucal cells in the gastric-intestinal tract, have lost their altruism, usually due to acquisition of tumor-driving mutations that make the cells egocentric.…”

Fucoidan Inhibition of Osteosarcoma Cells is Species and Molecular Weight Dependent

“…It is strongly argued that authentic apoptosis only occurs in the body and is irrelevant to non-renewable cell types, such as those used in vitro, as there is a lack of other cell types that play an important role in apoptosis [67]. Hence, stress-induced apoptosis-like cell death (SIaLCD) is often confused with apoptosis in most in vitro studies performed using cell lines [68][69][70]. Therefore, we postulate that MG63 cells underwent SIaLCD and not apoptosis in the present study.…”

Fucoidan Inhibition of Osteosarcoma Cells is Species and Molecular Weight Dependent

“…3% fucose, 20 ± 5% galactose, 2 ± 2% mannose, and 30 ± 3% sulphate) was also shown to induce apoptosis in MG63 osteosarcoma cells characterized by increased roundness of the cells due to accumulation of F-actin at the cortex and increased expression of Annexin V together with chromatin condensation[66].It is strongly argued that authentic apoptosis only occurs in the body and is irrelevant to nonrenewable cell types such as those used in vitro as there is a lack other cell types that play an important role in apoptosis[67]. Hence, stress induced apoptosis-like cell death (SIaLCD) is often confused with apoptosis in most in vitro studies performed using cell lines[68][69][70]. Therefore, we postulate that MG63 cells underwent SIaLCD and not apoptosis in the present study.…”