Chromosomal instability, associated with aggressive cancers, occurs due to the formation of fragile micronuclei, which rupture and release DNA into the cytosol, promoting mutations, inflammation, and resistance to therapies. Research also associates cannabis exposure with increased ROS, mitochondrial dysfunction, and micronucleus formation, resulting in risks of cancer, premature aging, and congenital anomalies, with transgenerational impacts that highlight the need for caution in legalization.
Chromosomal instability is a characteristic frequently associated with the most aggressive cancers. This condition is marked by the presence of structures called micronuclei, which are fragments of DNA formed by entire chromosomes or parts of chromosomes isolated from the main nucleus of the cell.
These micronuclei are fragile, with membranes prone to rupture, exposing the genetic content to the interior of the cell (the cytosol).
When the membranes of the micronuclei rupture, critical events occur that drive the progression of the cancer. DNA released into the cytosol can undergo severe changes, including genetic rearrangements (called chromothripsis) and epigenetic changes (modifications in the way genes are turned on or off).
Animal cell and its organelles. RUSSELL KIGHTLEY/SCIENCE SOURCE
These changes make tumors more diverse, resistant to therapy, and capable of spreading (metastasis). In addition, the disruption of micronuclei triggers inflammatory signals that change the environment around the tumor, further facilitating the progression of the disease.
However, the precise mechanisms behind the breakdown of micronuclei are still not fully understood.
A recent important discovery was made by scientists at Memorial Sloan Kettering Cancer Center. They investigated why micronuclei have such fragile membranes compared to the main nucleus of the cell.
They found that several unique characteristics of micronuclei contribute to their instability. They are 5 to 20 times smaller than the main nucleus, which can make it difficult for them to maintain a robust structure.
They also have less lamin B1, an essential structural protein, and have abnormal functions in their nuclear pores, which are "gates" that regulate the exchange of materials. Finally, once ruptured, the micronucleus membrane is rarely repaired, which worsens the damage.
The study revealed that the interaction between micronuclei and mitochondria (cellular structures that produce energy) plays a critical role in this rupture.
This process is mediated by reactive oxygen species (ROS), highly reactive molecules generated by mitochondria. ROS oxidizes components of the micronucleus, damaging proteins and promoting membrane collapse.
The researchers identified that high levels of ROS interfere with a repair system called ESCRT-III, which helps maintain the integrity of cell membranes. ROS accumulate in the micronucleus a protein called CHMP7, part of ESCRT-III.
Under normal conditions, this protein should be exported, but ROS blocks its exit, causing an aberrant binding with another protein, LEMD2, located in the inner nuclear envelope. This pathological interaction causes deformations in the membrane, resulting in its rupture.
Furthermore, ROS recruits a protein called p62, which degrades other ESCRT-III components, eliminating any chance for subsequent repair. These processes culminate in massive genetic damage, promoting tumor progression.
The study also showed that regions of human tumors with higher levels of ROS, such as those experiencing hypoxia (low oxygenation), have higher rates of micronucleus rupture and complex genetic alterations.
Complementary research conducted at the University of Western Australia explored another factor relevant to micronucleus formation: mitochondrial dysfunction induced by cannabis use.
Mitochondria
Studies indicate that cannabinoids can cause oxidative stress and direct mitochondrial damage, resulting in the formation of micronuclei and chromosome breaks.
Several epidemiological studies associate cannabis use with specific types of cancer, such as testicular cancer, lymphoma, and childhood cancers. The effects are potentially transmitted between generations.
In addition, exposure to cannabis is linked to the acceleration of epigenetic aging (changes in gene control), resulting in cellular aging. Defects such as cardiac, neurological, and limb malformations have been associated.
The study highlights that the genetic damage caused by cannabinoids is related to the chemical nucleus present in compounds such as THC, CBD, and others. These compounds induce the production of ROS, triggering effects similar to those observed in studies on micronuclei and mitochondria.
Furthermore, the increase in the potency of commercial cannabis in recent years may amplify these genotoxic effects.
Evidence suggests that the genotoxic effects of cannabis extend beyond the exposed individual, affecting future generations as well. This transgenerational impact includes genetic and epigenetic alterations that can manifest as cancer, premature aging, and birth defects.
For example, mutations associated with cannabis use have been identified in case studies involving early aggressive cancers, as well as morphological anomalies in eggs and sperm.
These findings reframe the debate over the legalization of cannabis, suggesting that its regulation should consider not only the immediate effects, but also the risks to the genomic integrity of future generations.
Mechanisms of micronuclear rupture. The proximity of mitochondria to micronuclei drives micronuclear membrane rupture via mitochondrial-derived reactive oxygen species (ROS). ROS inhibits micronuclear export, leading to excessive accumulation of CHMP7, a scaffolding protein associated with the nuclear membrane repair complex ESCRT-III. ROS-dependent cysteine oxidation promotes CHMP7 autoaggregation and its aberrant binding to the membrane protein LEMD2, causing micronuclear collapse.
READ MORE:
Micronuclear collapse from oxidative damage
Di Bona M et al.
SCIENCE. 2024. Vol 385, Issue 6712
DOI: 10.1126/science.adj8691
Abstract:
Chromosome-containing micronuclei are a hallmark of aggressive cancers. Micronuclei frequently undergo irreversible collapse, exposing their enclosed chromatin to the cytosol. Micronuclear rupture catalyzes chromosomal rearrangements, epigenetic abnormalities, and inflammation, yet mechanisms safeguarding micronuclear integrity are poorly understood. In this study, we found that mitochondria-derived reactive oxygen species (ROS) disrupt micronuclei by promoting a noncanonical function of charged multivesicular body protein 7 (CHMP7), a scaffolding protein for the membrane repair complex known as endosomal sorting complex required for transport III (ESCRT-III). ROS retained CHMP7 in micronuclei while disrupting its interaction with other ESCRT-III components. ROS-induced cysteine oxidation stimulated CHMP7 oligomerization and binding to the nuclear membrane protein LEMD2, disrupting micronuclear envelopes. Furthermore, this ROS-CHMP7 pathological axis engendered chromosome shattering known to result from micronuclear rupture. It also mediated micronuclear disintegrity under hypoxic conditions, linking tumor hypoxia with downstream processes driving cancer progression.
Key insights into cannabis-cancer pathobiology and genotoxicity
Albert Stuart Reece and Gary Kenneth Hulse
Addiction biology. Volume29, Issue11. November 2024. e70003
Abstract:
Whilst mitochondrial inhibition and micronuclear fragmentation are well established features of the cannabis literature mitochondrial stress and dysfunction has recently been shown to be a powerful and direct driver of micronucleus formation and chromosomal breakage by multiple mechanisms. In turn genotoxic damage can be expected to be expressed as increased rates of cancer, congenital anomalies and aging; pathologies which are increasingly observed in modern continent-wide studies. Whilst cannabinoid genotoxicity has long been essentially overlooked it may in fact be all around us through the rapid induction of aging of eggs, sperm, zygotes, foetus and adult organisms with many lines of evidence demonstrating transgenerational impacts. Indeed this multigenerational dimension of cannabinoid genotoxicity reframes the discussion of cannabis legalization within the absolute imperative to protect the genomic and epigenomic integrity of multiple generations to come.
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