Intergenerational Enlargement of Human Organs as a Driver of Increased Cancer Risk?

ABSTRACT

The incidence of multiple cancer types is increasing in younger generations, with the underlying causes being debated. Here, we propose that environmentally‐driven organ enlargement is a novel mechanism contributing to the observed increase in intergenerational cancer risk. All other things being equal, cancer risk will be higher in larger organs composed of more constituent cells, due to the lifetime accumulation of stochastic genomic replication errors. Importantly, the size of certain organs is affected by factors such as diet and lifestyle. Could distinct environmental conditions between generations, therefore, drive organ enlargement, and as a secondary effect, increase cancer risk? Average height and weight—which correlate to the size of internal organs—have clearly been increasing in more recent generations. Recent studies have also found that socio‐economic factors are associated with increased brain volume. Research to examine the validity and applicability of the proposed hypothesis could be highly important for public health policy.

Identifying the environmental factors and associated mechanisms driving increased cancer incidence in younger generations is a matter of great urgency. Here, we propose and discuss a new potential mechanism: larger organ sizes in younger individuals resulting from intergenerational differences in lifestyle, diet, and environmental exposures.

1. Introduction

An alarming pattern highlighted by recent epidemiological studies is the increased cancer incidence among younger generations compared to older cohorts [1, 2]. Beyond the immediate adverse effect of this trend, the rising incidence has the potential to lead to significant future cancer burden. Consequently, identification of the underlying aetiologias driving intergenerational increases of cancer incidence are of the highest importance for public health. Cancer risk factors function by either increasing the incidence of genetic mutations or by promoting a more tumor‐favorable environment for the incipient cancer cells. Along this paradigm, exposures to environmental mutagens, such as medical radiological imaging [3] and environmental pollution [4], have been proposed as drivers of increased intergenerational cancer incidence due to their mutagenic effects. Alternatively, obesity and sedentary lifestyles have also been associated with cancer risk through multiple mechanisms, including the promotion of inflammation, immune dysregulation, and hormonal imbalances [5, 6, 7]. Identifying and quantifying the impact of risk factors to rising cancer incidence in the younger generations will be important for designing public health policies to reverse this trend, as has been achieved previously through anti‐smoking campaigns and HPV vaccination [8, 9].

Here we propose a novel carcinogenic mechanism as a contributor to the increased intergenerational cancer risk, namely the enlargement of organ sizes in younger generations due to the exposure to distinct environmental conditions.

2. For Cancer, Organ Sizes Do Matter

A central aspect of cancer is the presence of mutations that disrupt the normal functioning of oncogenes and tumor suppressor genes [10]. These mutations can be inherited, caused by exposure to exogenous factors, or be the result of endogenous cellular processes. For example, the faithful replication of the entire genome [11], that for humans consists of ∼ 3 × 10⁹ bases [12], is essential during each cell cycle. A major source of endogenously caused mutations is errors occurring during this process, caused by, among others, aberrant topoisomerase activity, R loop formation, strand slippage events, and spontaneous base deamination [13, 14]. Consequently, DNA replication plays a major role in mutagenesis, and therefore, ultimately cancer. In agreement with this view, mutational signatures in cancer are associated with DNA replication timing and strand symmetry [15], and variability in tumor incidence between organs of mice and men correlates with the accumulated stem cell divisions occurring throughout their lifetimes [16, 17, 18].

If cell divisions are a major source of endogenous mutations that allow cancer clonal evolution to occur, what happens when the size of a given organ differs between individuals or populations? Organs can become larger through hypertrophy—that is, larger cells—or by increasing their number of constituent cells. The latter path will necessarily entail the organ's progenitor cells undergoing more divisions to generate the additional constituent cells. Additionally, numerically greater cell divisions will also be required to maintain homeostasis for larger mature human organs throughout a lifetime [19]. Consequently, larger organs composed of more cells will undergo a greater number of cell divisions throughout their lifetime, increasing the rate of stochastic mutagenesis and of cancer risk (Figure 1).

FIGURE 1.

Schematic diagram of the association between organ size and stochastic mutational events. Mitotic cell divisions are required to form mature organs from their precursor cells. Full‐size mature organs also require mitotic cell divisions in order to compensate for cellular turnover. As organ size increases, a cumulatively greater number of mitotic divisions will be required for their formation and homeostasis. Significantly, cell divisions are associated with stochastic mutations (symbolized here by a lightning symbol). It can be expected, therefore, that a greater number of mutational events will accumulate in larger organs.

2.1. Environmental Intergenerational Differences Affect Organ Sizes, and Therefore Potentially Cancer Risk

The regulation of adult organ sizes is complex and incompletely understood [20]. For some organs like the pancreas, the adult size is fixed and determined by the number of embryonic progenitor cells [21]. Many other organs, however, display a degree of size malleability in response to environmental conditions, either in utero or during postnatal life. Growth factors, nutrients, mechanical forces, and cell densities, among others, affect organ sizes through their effects on pathways such as Hippo and mTOR [20, 22]. Examples of organ sizes responding to environmental conditions include increased muscle hypertrophy following resistance exercise [23], bone mass loss in astronauts due to reduced mechanical stress [24], negative feedback by bile acids on the liver [25], and chronic stress on adrenal glands [26].

If, as we have seen, environmental factors can affect organ sizes within a lifetime and between individuals, could they also drive intergenerational differences? That would require that environmental factors possessing such properties vary in biologically meaningful degree between human generations. We propose that this has indeed been the case, and discuss prime candidates below.

2.2. Western Diets and Lifestyle Affecting Height and Bodyweight

Profound changes in the human environment have occurred since the industrial revolution, including total calorie intake, diet diversity, physical activity, sun exposure, and sleep patterns [27]. These environmental factors have clearly affected the human body type compared to previous generations. Obvious and dramatic among them has been the increase in average height recorded in most regions of the world, with up to 20 cm for some populations [28]. Factors such as increased protein intake drive growth hormones and other biological responses underlying the trend for increased height [29]. Another environmental factor that has affected adult height is the reduced burden of infant and childhood infections [30]. A reasonable assumption is that at least some of the internal organs will on average be enlarged in taller individuals. Bone length is highly correlated with height [31] relating to structural support offered by the skeleton. Internal organs may also correlate with height due to the requirement to fulfil increased metabolic and biophysical demands, as has been reported for the liver [32] and spleen [33] among others.

Another recognized body trend of the modern age is the prominent rise in obesity throughout the developed world [34]. Obesity has widespread effects on the body and internal organs through a variety of mechanisms, including due to body scaling, increased metabolic demands, hormonal imbalances, and chronic inflammation [35]. In mice, over‐eating and obesity lead to enlargement of the liver, heart, and kidneys [36]. A recent imaging study of humans has reported a linear relationship between BMI and the volumes of kidneys, liver, and pancreas [37]. Thus, both average height and bodyweight have been increasing in recent generations—driven by environmental factors—and correlate with enlargement of human organs.

2.3. Socioeconomic Factors and Brain Size

Less widely appreciated is the trend for intergenerational increase in brain sizes driven by improved socioeconomic conditions. Neuroimaging methodologies have been developed for the measurement of brain volume and structure and are routinely gathered for the diagnosis of neurological disorders and studies into development and function of the organ. In a recent study, DeCarli et al. reported an MRI cross‐sectional study as part of the Framingham Heart Study cohort of participants born between 1925 and 1968, finding significant increases in intracranial volume (ICV), white matter, hippocampal volume, and cortical surface area [38]. A large examination of UK biobank data revealed the contribution of both genetic and environmental factors to human brain anatomy [39]. However, such rapid increases in brain size cannot be attributed to genetics, but are more likely explained by improved socioeconomic status [40]. Consequently, for the brain, we already have solid data for an environmentally driven intergenerational size increase. Notably, MRI scans find a significant correlation between ICV and glioblastoma incidence, with the mean volume in female patients with high‐grade glioma being 55 mL larger than in female controls, and with each 100 mL increase in ICV, a person having 1.69 times higher odds ratio (OR) (95% CI: 1.44–1.98, p < 0.001) [41].

2.4. Epidemiological Support and Confounders

We have discussed above plausible axes through which modern life conditions can drive increased organ sizes, and subsequently, cancer risk. Increased protein intake and reduced infection burden have allowed the recent dramatic increases in human height. Similarly, more sedentary lifestyles and increased calorie intake, among other factors, are major causes of rising obesity. Correlations between both height and obesity with the size of internal organs have repeatedly been found in post‐mortem and imaging studies. Socioeconomic factors are also linked to increased brain size, and neuroimaging studies have revealed this trend across human generations (Figure 2). It is also possible that other environmental conditions associated with modern life could be interacting with our body structure and composition (e.g., transgenerational inheritance, microbiota‐derived hormones, and pollutants), although we will not expand further here on such speculations.

FIGURE 2.

Candidate environmental‐drivers of intergenerational increase in organ size. The diet, lifestyle, and socioeconomic changes associated with the Industrial and Modern Ages have driven increased height, bodyweight, and brain sizes in more recent generations. A number of studies have reported correlations between height or bodyweight with internal organ sizes, while recently, a trend for increase in brain size has also been identified.

It is interesting to note that epidemiological studies support the association of obesity and height with higher cancer incidence [42, 43]. For obesity a causal link was supported with 13 cancer types [42]. For height the hazard ratio for overall cancer risk has been estimated to increase by 10% for every extra 10 cm of height [43]. Additionally, a number of studies have reported an increased incidence of glioblastoma in younger generations [44, 45].

It must be noted, however, that there are important confounders and caveats in extrapolating from epidemiological studies to confirmation of our proposed hypothesis. For obesity and height, alternative carcinogenic mechanisms have been proposed and are likely applicable to a degree, for example, obesity‐induced inflammation and higher circulating IGF‐1 associated with height. For glioblastoma, the increased incidence could be the result of unidentified environmental agents or some currently unrecognized mechanism. Nevertheless, it can be stated that the current epidemiological studies are at a minimum consistent with the proposed mechanism.

3. Evaluation of the Hypothesis

Our hypothesis is grounded on the following propositions and observations: (a) that environmental exposures in utero or in early life underlie a trend toward larger adult sizes for some organs in younger human generations; (b) that all other things being equal, cancer incidence will be enhanced in larger organs due to the associated increase in cell number/divisions and stochastic mutagenic events during genomic replication; and (c) that investigations have found relationships between organ sizes and cancer risk. We propose the following research avenues to assess the validity of these propositions.

3.1. Improved Measurements on Internal Organ Size Increases Across Generations

Access to more accurate and greater number of data comparing internal organ sizes between human generations will be highly beneficial for the context of the proposed hypothesis. First, more precise organ measurements will pinpoint those undergoing intergenerational changes in size, and therefore those for which the proposed hypothesis is more likely to be relevant. Second, better measurements of organ sizes and the increase in parenchymal cell number will be essential for computational modelling of the impact on cancer risk and forecasting future incidence and prevalence.

The most direct method for measuring organ size is their examination outside the human body. This can occur, for example, by investigations of internal organs post‐mortem or of organs collected for the purpose of transplantation. This approach, however, has limitations relating to ethical considerations and the need for consent. An alternative non‐invasive approach to measuring internal organs is the use of imaging technologies such as computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound. Importantly, these technologies are currently in the process of significant automation and refinement through the development and integration of artificial intelligence (AI) and deep learning algorithms [46, 47]. Further refinement and application of these tools will most likely generate more and improved data on organ measurements in the coming years, making them a highly valuable resource for assessing the proposed hypothesis.

3.2. Epidemiological and Longitudinal Studies

Improved imaging technologies will also be highly beneficial for conducting epidemiological and longitudinal studies. Large‐scale epidemiological studies can reveal associations between organ size and cancer incidence. Additionally, epidemiological studies can also reveal environmental factors regulating organ sizes, even ones that are not currently being considered.

Another line of investigation is to examine whether genes and pathways regulating organ size are associated with cancer risk using approaches such as Mendelian randomization. Finally, longitudinal studies measuring organ size and tracking cancer incidence within the same individuals over time will be a powerful tool for testing their potential association.

3.3. Molecular and Experimental Investigations

One prediction of our hypothesis is that a greater tissue mutational burden associated with cellular replication will be found for organs displaying intergenerational size increase. This prediction can be assessed by single‐cell sequencing using organ material samples from different generations. For example, we expect to observe on average more mutations in brain tissue samples from more recent generations; that the mutational burden will be associated with signatures of DNA replication and not of exposure to environmental agents; and that mutational burden will correlate with organ size.

Mechanistic testing of the hypothesis could also be pursued through the manipulation of organ size in animal models, followed by assessments of mutation rates and cancer incidence. Currently, though, such experimental investigations are hindered by our incomplete understanding of the molecular mechanisms controlling organ size [20].

3.4. Implications of the Hypothesis on Public Health Policies

An important implication of our hypothesis is that trends for increased intergenerational organ sizes will be associated with increased cancer incidence in younger generations. This increase could counter other public health efforts to reduce cancer burden that are already underway. Evaluation and quantification of the contribution of intergenerational organ size increases to cancer incidence will require the use of mathematical models that will consider the increase in the number of cells and cell divisions across lifetime, and how this can be used to predict cancer incidence. For this purpose, more concerted efforts to evaluate and quantify alterations in organ size between generations—besides the brain—are also needed. For example, which organs have been trending toward larger sizes in response to obesity and height increases, and by how much? This information can be highly informative in identifying individuals to be prioritized for cancer screening and for estimating future cancer burden. We consider, therefore, that allocating more resources to test and refine the proposed novel carcinogenic mechanism is valid. Another implication of the presented hypothesis is that interventions that restrain organ size will have a measurable effect on cancer incidence. For certain cases, such as obesity, interventions would be beneficial not only for reducing cancer but for the general health and well‐being of individuals. However, in other cases, such as the brain it is unlikely to be a practical or desirable strategy for reducing glioblastoma incidence. Among other reasons, larger brain size is beneficial in other contexts, such as in reducing the risk of dementia [48]. Similarly, it is unlikely that interventions to reduce adult height—by reducing protein in diet, for example—will be considered practical or desirable.

4. Conclusion

Identifying and quantifying the drivers of increased cancer incidence is an urgent matter of public policy. Here, we propose environmentally‐driven increases in organ size as a plausible contributor to the observed cancer incidence in recent generations. While our hypothesis may help explain observed differences in cancer risk between human generations, it does not exclude the involvement of other carcinogenic mechanisms. Indeed, in certain contexts, environmental factors may increase cancer risk by acting through multiple mechanisms. For example, obesity may promote larger organ sizes but additionally is favorable for inflammation. Elucidating the underlying causes of the observed cancer risk in younger generations is an urgent matter for identifying high‐risk individuals and, where possible, intervention strategies.

Author Contributions

C.K. and V.N. conceptualized the idea, drafted, and revised the manuscript.

Conflicts of Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data Availability Statement

Data sharing not applicable to this article, as no datasets were generated or analyzed during the current study.