{"id":18368,"date":"2024-11-24T18:49:30","date_gmt":"2024-11-24T17:49:30","guid":{"rendered":"https:\/\/drugprevent.org.uk\/ppp\/?p=18368"},"modified":"2025-02-02T17:54:26","modified_gmt":"2025-02-02T16:54:26","slug":"key-insights-into-cannabis-cancer-pathobiology-and-genotoxicity","status":"publish","type":"post","link":"https:\/\/drugprevent.org.uk\/ppp\/2024\/11\/key-insights-into-cannabis-cancer-pathobiology-and-genotoxicity\/","title":{"rendered":"Key insights into cannabis-cancer pathobiology and genotoxicity"},"content":{"rendered":"\n\n\n
\"\"<\/a><\/strong><\/td>\n\u00a0– PERSPECTIVE<\/strong><\/span><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

\u00a0<\/strong>CO-AUTHORS:<\/strong><\/p>\n

Albert Stuart Reece1,2 | Gary Kenneth Hulse1,2
\n1University of Western Australia, Crawley,
\nWestern Australia, Australia<\/p>\n

2School of Health Sciences, Edith Cowan
\nUniversity, Joondalup, Western Australia,
\nAustralia<\/p>\n

Correspondence:<\/strong>
\nAlbert Stuart Reece, University of Western
\nAustralia, 35 Stirling Hwy, Crawley, WA 6009,
\nAustralia.
\nEmail: stuart.reece@uwa.edu.au<\/p>\n

ABSTRACT:<\/strong><\/span><\/p>\n

Whilst mitochondrial inhibition and micronuclear fragmentation are well established
\nfeatures of the cannabis literature mitochondrial stress and dysfunction has recently
\nbeen shown to be a powerful and direct driver of micronucleus formation and chromosomal
\nbreakage by multiple mechanisms. In turn genotoxic damage can be
\nexpected to be expressed as increased rates of cancer, congenital anomalies and
\naging; pathologies which are increasingly observed in modern continent-wide studies.
\nWhilst cannabinoid genotoxicity has long been essentially overlooked it may in fact
\nbe all around us through the rapid induction of aging of eggs, sperm, zygotes, foetus
\nand adult organisms with many lines of evidence demonstrating transgenerational
\nimpacts. Indeed this multigenerational dimension of cannabinoid genotoxicity
\nreframes the discussion of cannabis legalization within the absolute imperative to
\nprotect the genomic and epigenomic integrity of multiple generations to come.<\/p>\n

KEYWORDS:\u00a0 \u00a0<\/strong>cannabis, chromothripsis, micronucleus<\/p>\n

\n

MAIN ARTICLE TEXT:<\/strong><\/p>\n

Recent papers in Science provide penetrating and far-reaching insights
\ninto the mechanisms underlying micronuclear rupture a key genotoxic
\nengine identified in many highly malignant tumours.1,2 Reactive
\noxygen species (ROS) generated either by damaged mitochondria or
\nthe hypoxic tumour microenvironment were shown to damage micronuclear
\nenvelopes, which made them more sensitive to membrane
\nrupture. Damage occurred by both increased susceptibility to membrane
\nrupture and impaired membrane repair. Micronuclear rupture is
\nknown to be associated with downstream chromosomal shattering,
\npan-genome genetic disruption by chromothripsis, widespread epigenetic
\ndysregulation and cellular ageing. Clinical expressions of genotoxicity
\nare expected to appear as cancer, birth defects and ageing.
\nCHMP7 (charge multivesicular body protein 7) oxidation caused
\nheterodimerization by disulphide crosslinking and aberrant crosslinking
\nwith membrane bound LEMD2 (LEM-domain nuclear envelope
\nprotein 2) inducing membrane deformation and collapse. ROS-CHMP7
\ndirectly induced chromosomal shattering. Oxidized CHMP7 bound
\ncovalently to the membrane repair scaffolding protein ESCRT-III
\n(endosomal sorting complex required for transport\u2013III). ROS triggered
\nhomo-oligomerization of the autophagic receptor p62\/sequestome
\nre-routing the CMPH7-ESCRT-III complex away from membrane
\nrepair into macroautophagy via the autophagosome and microautophagy
\nvia lysozomes.1\u20133 Expected downstream consequences of
\nmicronuclear rupture including chromosomal fragmentation, chromothripsis
\nand cGAS-STING (cyclic adenosine-guanosine synthase\u2013
\nstimulator of interferon signalling) activation were demonstrated.
\nCancer-related innate inflammation is known to drive tumour progression
\nand distant metastasis. These principles were tested both in normal
\nand also numerous malignant (including head and neck squamous,
\ncervical, gastric, ovarian and colorectal cancers) cell lines.1,2 Similar
\nprocesses including DNA damage and epigenomic derangements have
\nalso been identified in TH1-lymphocytes during fever indicating that
\nmitochondriopathic-genotoxic mechanisms may in fact be widespread
\nand fundamental.4<\/p>\n

\n

Received: 26 September 2024 Accepted: 26 September 2024
\nDOI: 10.1111\/adb.70003
\nThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.<\/p>\n

\n

 <\/p>\n

Addiction Biology. 2024;29:e70003. wileyonlinelibrary.com\/journal\/adb
\nhttps:\/\/doi.org\/10.1111\/adb.70003<\/p>\n

\n

Cannabis has been known to be linked with both micronuclear
\ndevelopment and mitochondrial inhibition for many decades.5,6
\nAll cannabinoids have been implicated in genotoxicity as the moiety
\nidentified as damaging the genetic material is the central olivetol
\nnucleus on the C-ring itself.7 This finding implicates \u03948-, \u03949-, \u039410-,
\n\u039411-tetrahydrocannabinol, cannabigerol, cannabidiol and cannabinol
\namongst all other cannabinoids.
\nHistorically, the cancer-cannabis link has been controversial. Differing
\nresults in published studies may be attributed to various factors
\nincluding multiple exposures (including tobacco), differences in
\nstudy design and the rapid rise of cannabis potency. One often quoted
\nstudy actually specifically excluded high level cannabis exposure, which
\nwould now appear to have been a major methodological limitation.8 It
\nis widely documented that there has been a sharp increase in cannabis
\nconcentration from the 1970s to the present day. THC concentrations
\nof 25%\u201330% are commonly noted in cannabis herb and flower sold
\ncommercially, and 100% THC concentrations are well known for cannabinoid
\nbased products such as dabs, waxes and \u2018shatter\u2019.
\nIn this context, the recent appearance of a series of continentwide
\nepidemiological, space\u2013time and causal inferential studies in
\nboth Europe and North America is notable for many positive signals
\nfor various cancers including breast, pancreas, liver, AML, thyroid, testis,
\nlymphoma, head and neck squamous cancer, total childhood cancer
\nand childhood ALL.9\u201315 The literature on cannabis and testicular
\ncancer is almost uniformly positive and has a relative risk of around
\n2.6-fold,16 this risk factor is now widely acknowledged17\u201319 and the
\neffect is quite fast since the median age of exposure may be about
\n20 years and the median age of testis cancer incidence is only
\n31 years. Testicular cancer is the adult cancer responsible for the most
\nyears of life lost.17,18,20,21 The inclusion of several childhood cancers
\nin association with cannabis exposure obviously implicates transgenerational
\ntransmission of malignant mutagenesis.
\nAn intriguing finding in the case report literature is that in many
\ncases, cancers occur decades earlier and are very aggressive at diagnosis.
\n22 Mechanisms such as the synergistic mitochondriopathic\u2013
\nmicronuclear axis presently proposed in the recent Science papers1\u20134
\nmay directly explain this very worrying observation.
\nWhilst cancer is thought to be a rare outcome amongst cannabis
\nexposed individuals, ageing effects are not. A dramatic acceleration
\nof cellular epigenetic age by 30% at just 30 years was recently
\nreported23 with indications this effect likely rises with age,24 and
\nthe demonstration that cannabis exposed patients had adverse
\noutcomes across a wide range of physical and mental health outcomes
\nincluding myocardial infarction and emergency room presentations.
\n25 Importantly, the ageing process itself has been shown to
\nbe due to redistribution of the epigenetic machinery in such a manner
\nas to produce dysregulation (and widespread reduction) of gene
\nexpression and to be inducible by limited genetic damage resulting
\nfrom just a handful of DNA breaks.26 Extremely worryingly, agerelated
\nmorphological changes have been described in both oocytes
\nand sperm.27,28
\nEpidemiological studies of European and American cannabiscancer
\nlinks are supported by epidemiological, space\u2013time and causal
\ninferential studies of links between cannabis and congenital
\nanomalies.29\u201333 Reported congenital anomalies are clustered in the
\ncardiovascular, neurological, limb, chromosomal, urogenital and gastrointestinal
\nsystems. The fact that all five chromosomal anomalies
\nstudied here are represented in this list, notwithstanding their high
\nrate of known foetal loss, is strong evidence for chromosomal misegregation
\nduring germ cell meiosis, which is the genetic precursor to
\nmicronucleus development.34,35 The fact that almost identical results
\nwere reported in both the United States and Europe provides strong
\nexternal validation to these findings.30
\nThis is consistent with recent press reports of dramatic increases
\nin babies and calves born without limbs in both France and
\nGermany36,37 raising the public health spectre of downstream implications
\nof food chain contamination. Melbourne, Australia, is a multiethnic
\ncity, which heads the global leaderboard for babies born with
\nthe serious limb anomalies amelia and phocomelia.37\u201340 This pattern
\nof elevated rates of major birth defects is not seen in the host nations
\nfrom which these migrant populations are derived. Cannabis farms are
\nincreasingly common around Melbourne, just as they are in the
\nFrench province of Ain, which has similar concerns.37,41\u201343
\nMajor epigenetic changes have been found in human sperm,44
\nwhich have also been identified in exposed rodent offspring.44\u201346
\nIndeed, 21 of the 31 congenital anomalies described following prenatal
\nthalidomide exposure have also been observed epidemiologically
\nfollowing prenatal cannabis exposure and 12 of 13 cellular pathways
\nby which thalidomide operates have been similarly identified in the
\ncannabis mechanistic literature.47 Both human and rodent epigenomic
\nstudies44\u201346 and epidemiological studies show that adult cannabis
\nexposure is linked with the incidence of autism48\u201353 and cerebral processing
\ndifficulties54\u201357 in children prenatally exposed. Together, this
\ndata is clear and robust evidence for the transgenerational transmission
\nof major genotoxic outcomes.
\nNotwithstanding the well-known ambiguities in the epidemiological
\nliterature for cannabis, it is clear from the above brief overview
\nthat there is strong and compelling evidence that cannabis genotoxic
\noutcomes are well substantiated and form a remarkably congruent
\nskein of interrelated evidence across all three domains of genotoxic
\npathology including cancer, congenital anomalies and ageing.
\nSo too compelling epidemiological, morphological and epigenetic
\nevidence of transgenerational transmission of cannabinoid genotoxicity
\nto foetus, egg, sperm and offspring carries far reaching and
\ntransformative implications and indeed reframes the discussion surrounding
\ncannabis legalization from merely personal-hedonistic to the
\nprotection of the national genomic integrity for multiple subsequent
\ngenerations.
\nThe present time therefore represents a watershed moment.
\nThe new profoundly insightful studies from Science point the way and
\nprovide the trigger. Clearly, there is a great need for a new
\nand updated cohort of epidemiological studies on these issues at the
\npopulation level in the modern context of the widespread availability
\nof much more potent cannabinoid preparations.
\nHowever, our first responsibility is to act on the evidence we do
\nhave. Given the uniform picture painted by data from myriad directions.<\/p>\n

It can be said that the evidence for cannabinoid genotoxicity
\nis at once so clinically significant, robust and compelling as to constitute
\na resounding clarion call to action: The only outstanding
\nquestion is \u2018Will we rise to the challenge?\u2019<\/p>\n

\n

13691600, 2024, 11, Downloaded from https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/adb.70003 by National Health And Medical Research Council, Wiley Online Library on [14\/11\/2024]. See the Terms and Conditions (https:\/\/onlinelibrary.wiley.com\/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License<\/p>\n

\n

 <\/p>\n

CONFLICT OF INTEREST STATEMENT:<\/strong>
\nThe authors declare no conflicts of interest.<\/p>\n

ORCID:<\/strong>
\nAlbert Stuart Reece https:\/\/orcid.org\/0000-0002-3256-720X<\/p>\n

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\nHow to cite this article: Reece AS, Hulse GK. Key insights into
\ncannabis-cancer pathobiology and genotoxicity. Addiction
\nBiology. 2024;29(11):e70003. doi:10.1111\/adb.70003<\/p>\n

13691600, 2024, 11, Downloaded from https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/adb.70003 by National Health And Medical Research Council, Wiley Online Library on [14\/11\/2024]. See the Terms and Conditions (https:\/\/onlinelibrary.wiley.com\/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License<\/p>\n

Source:\u00a0<\/strong><\/span>ORCID, Inc <\/strong>10411 Motor City Drive, Suite 750, Bethesda, MD 20817, USA<\/p>\n","protected":false},"excerpt":{"rendered":"

\u00a0– PERSPECTIVE \u00a0CO-AUTHORS: Albert Stuart Reece1,2 | Gary Kenneth Hulse1,2 1University of Western Australia, Crawley, Western Australia, Australia 2School of Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia Correspondence: Albert Stuart Reece, University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009, Australia. Email: stuart.reece@uwa.edu.au ABSTRACT: Whilst mitochondrial inhibition and micronuclear fragmentation are well […]<\/p>\n","protected":false},"author":4,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[15,30,68,60,19],"tags":[],"class_list":["post-18368","post","type-post","status-publish","format-standard","hentry","category-australia","category-cannabis-marijuana","category-drug-use-various-effects","category-marijuana-and-medicine","category-usa"],"_links":{"self":[{"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/posts\/18368","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/users\/4"}],"replies":[{"embeddable":true,"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/comments?post=18368"}],"version-history":[{"count":0,"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/posts\/18368\/revisions"}],"wp:attachment":[{"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/media?parent=18368"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/categories?post=18368"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/tags?post=18368"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}