Shrinking to bird size with dinosaur-level cancer defences

 

. 2025 Sep 9;21(9):e1013432. doi: 10.1371/journal.pcbi.1013432

Shrinking to bird size with dinosaur-level cancer defences: Evolution of cancer suppression over macroevolutionary time

E Yagmur Erten 1,2,3,4,*, Marc Tollis 2,5, Hanna Kokko 1,6,7

Editor: 

Abstract

Ubiquity of cancer across the tree of life yields opportunities to understand variation in cancer defences across species. Peto’s paradox, the finding that large-bodied species do not suffer from more cancer despite having more cells at risk of oncogenic mutations compared to small species, can be explained if large size selects for better cancer defences. Since birds live longer than non-flying mammals of equivalent size, and are descendants of moderate-sized dinosaurs, we ask whether ancestral cancer defences are retained if body size shrinks in a lineage. Our model derives selection coefficients and fixation events for changes in cancer defences over macroevolutionary time, based on known relationships between body size, cancer risk, extrinsic mortality, metabolic rate, and effective population size. We show that, if mutation rate is sufficiently high and cancer defences are costly, we expect birds to have lower cancer defences than their dinosaurian ancestors. However, if the evolution of cancer suppression is mutation limited, due to e.g. pleiotropy, birds may have kept excessive dinosaurian cancer defences, possibly explaining their low cancer risk. Counterintuitively, birds can then be ‘too robust’ for their own good, if excessive cancer suppression requires compromising reproductive rates. Yet, evolutionary innovations such as flight can increase longevity and keep selection for cancer suppression intact in birds, even if flight requires small body size. Retaining dinosaur-level cancer defences can then be adaptive, particularly if the evolution of flight is accompanied by an increase in cancer risk due to metabolic scaling. Overall, our study suggests that studying cancer suppression in birds can reveal alternative mechanisms to those found in mammals, possibly inherited from birds’ dinosaurian ancestors.

Author summary

Humans are not the only species suffering from cancer, yet cancer does not impact all life equally. Body size is relevant because maintaining a large number of cells in a tumour-free state necessitates improved cancer defences. Present-day birds appear adept at avoiding cancer, and live longer than similarly sized mammals. Since birds arose from a large-bodied dinosaur lineage rather than having always been small, we ask if evolutionary lags might explain their superior cancer defences. We model the circumstances under which dinosaurian anti-cancer innovations can still persist, making birds more cancer-resistant and longer-lived than mammals. We show that unless the process is mutation-limited, dinosaur-level cancer defences will decay over macroevolutionary time. However, evolutionary lags, when they do occur, can render birds cancer-robust and explain their relatively long lifespans. Eroding defences is made less likely by evolution of flight, which by reducing extrinsic mortality risk can make long lifespans feasible, and by metabolic scaling during shrinkage, if increasing mass-specific metabolic rate translates into an increase in the rate of cancer-causing mutations.

 

पीएलओएस कॉम्प्युटेशनल बायोलॉजी

. २०२५ सप्टेंबर ९; २१(९):ई१०१३४३२. डीओआय: १०.१३७१/जर्नल.पीसीबीआय.१०१३४३२

डायनासोर-स्तरीय कर्करोग संरक्षणासह पक्ष्याच्या आकारापर्यंत आकुंचन:

 महाउत्क्रांतीच्या काळात कर्करोग दमनाची उत्क्रांती

ई यागमूर एर्टेन १,२,३,४,*, मार्क टोलिस २,५, हॅना कोक्को १,६,७

संपादक:

PLoS Comput Biol

. 2025 Sep 9;21(9):e1013432. doi: 10.1371/journal.pcbi.1013432

Shrinking to bird size with dinosaur-level cancer defences: Evolution of cancer suppression over macroevolutionary time

E Yagmur Erten 1,2,3,4,*, Marc Tollis 2,5, Hanna Kokko 1,6,7

Editor: 

सारांश

जीवनाच्या वृक्षावर कर्करोगाची सर्वव्यापकता, विविध प्रजातींमधील कर्करोग संरक्षणातील भिन्नता समजून घेण्याची संधी देते. पेटोचा विरोधाभास, म्हणजेच लहान प्रजातींच्या तुलनेत मोठ्या शरीराच्या प्रजातींमध्ये ऑन्कोजेनिक उत्परिवर्तनाचा धोका असलेल्या पेशी जास्त असूनही त्यांना जास्त कर्करोग होत नाही, याचे स्पष्टीकरण असे दिले जाऊ शकते की मोठा आकार चांगल्या कर्करोग संरक्षणासाठी निवड करतो. पक्षी हे त्यांच्या समान आकाराच्या उडू न शकणाऱ्या सस्तन प्राण्यांपेक्षा जास्त काळ जगतात आणि ते मध्यम आकाराच्या डायनासोरचे वंशज आहेत, म्हणून आम्ही असा प्रश्न विचारतो की, जर एखाद्या वंशात शरीराचा आकार लहान झाला, तर पूर्वजांमधील कर्करोगापासून बचावाच्या यंत्रणा टिकून राहतात का. आमचे मॉडेल, शरीराचा आकार, कर्करोगाचा धोका, बाह्य मृत्यूदर, चयापचय दर आणि प्रभावी लोकसंख्येचा आकार यांच्यातील ज्ञात संबंधांवर आधारित, महाउत्क्रांतीच्या काळात कर्करोगापासून बचावाच्या यंत्रणांमध्ये होणाऱ्या बदलांसाठी निवड गुणांक आणि स्थिरीकरण घटना निश्चित करते. आम्ही दाखवतो की, जर उत्परिवर्तनाचा दर पुरेसा जास्त असेल आणि कर्करोगापासून बचावाच्या यंत्रणा खर्चिक असतील, तर पक्ष्यांमध्ये त्यांच्या डायनासोर पूर्वजांपेक्षा कर्करोगापासून बचावाच्या यंत्रणा कमी असण्याची अपेक्षा आहे. तथापि, जर कर्करोग प्रतिबंधाची उत्क्रांती उत्परिवर्तनाने मर्यादित असेल, उदाहरणार्थ बहुप्रभावीपणामुळे, तर पक्ष्यांनी डायनासोरच्या काळातील अतिरिक्त कर्करोग प्रतिबंधाच्या यंत्रणा टिकवून ठेवल्या असतील, ज्यामुळे त्यांच्यातील कर्करोगाचा कमी धोका स्पष्ट होऊ शकतो. विरोधाभासाने, जर अतिरिक्त कर्करोग प्रतिबंधासाठी प्रजनन दराशी तडजोड करणे आवश्यक असेल, तर पक्षी त्यांच्या स्वतःच्या फायद्यासाठी 'जास्तच कणखर' असू शकतात. तरीही, उड्डाणासारख्या उत्क्रांतीतील नवनवीन शोधांमुळे पक्ष्यांचे आयुष्य वाढू शकते आणि कर्करोग प्रतिबंधासाठीची निवड कायम राहू शकते, जरी उड्डाणासाठी लहान शरीराची आवश्यकता असली तरी. डायनासोरच्या पातळीवरील कर्करोग संरक्षण टिकवून ठेवणे हे अनुकूलनक्षम ठरू शकते, विशेषतः जर उड्डाणाच्या उत्क्रांतीसोबत चयापचयाच्या प्रमाणबद्धतेमुळे (metabolic scaling) कर्करोगाचा धोका वाढला असेल. एकंदरीत, आमचा अभ्यास असे सुचवतो की पक्ष्यांमधील कर्करोग प्रतिबंधाचा अभ्यास केल्यास सस्तन प्राण्यांमध्ये आढळणाऱ्या यंत्रणांपेक्षा वेगळ्या यंत्रणा उघड होऊ शकतात, ज्या कदाचित पक्ष्यांच्या डायनासोर पूर्वजांकडून वारसा म्हणून मिळाल्या असतील.

लेखकाचा सारांश

केवळ मानवच कर्करोगाने ग्रस्त असलेली प्रजाती नाही, तरीही कर्करोगाचा परिणाम सर्व जीवांवर समान होत नाही. शरीराचा आकार महत्त्वाचा आहे, कारण मोठ्या संख्येने पेशींना ट्यूमर-मुक्त अवस्थेत ठेवण्यासाठी सुधारित कर्करोग संरक्षणाची आवश्यकता असते. सध्याचे पक्षी कर्करोग टाळण्यात पारंगत दिसतात आणि त्याच आकाराच्या सस्तन प्राण्यांपेक्षा जास्त काळ जगतात. पक्षी नेहमीच लहान नसून मोठ्या शरीराच्या डायनासोरच्या वंशातून उत्क्रांत झाले असल्याने, आम्ही विचारतो की त्यांच्या उत्कृष्ट कर्करोग संरक्षणाचे स्पष्टीकरण उत्क्रांतीतील विलंबामुळे (evolutionary lags) देता येईल का. आम्ही अशा परिस्थितीचे मॉडेल तयार करतो, ज्यात डायनासोरच्या काळातील कर्करोग-विरोधी नवकल्पना अजूनही टिकून राहू शकतात, ज्यामुळे पक्षी सस्तन प्राण्यांपेक्षा अधिक कर्करोग-प्रतिरोधक आणि दीर्घायुषी बनतात. आम्ही दाखवतो की जोपर्यंत ही प्रक्रिया उत्परिवर्तनाने (mutation) मर्यादित होत नाही, तोपर्यंत डायनासोरच्या पातळीवरील कर्करोग संरक्षण महा-उत्क्रांतीच्या (macroevolutionary) काळात क्षीण होईल. तथापि, जेव्हा उत्क्रांतीमध्ये विलंब होतो, तेव्हा तो पक्ष्यांना कर्करोगाला प्रतिकारक्षम बनवू शकतो आणि त्यांच्या तुलनेने दीर्घ आयुर्मानाचे स्पष्टीकरण देऊ शकतो. उडण्याच्या उत्क्रांतीमुळे संरक्षण यंत्रणा क्षीण होण्याची शक्यता कमी होते, कारण उडण्यामुळे बाह्य मृत्यूचा धोका कमी होऊन दीर्घायुष्य शक्य होऊ शकते. तसेच, आकार कमी होत असताना होणाऱ्या चयापचयाच्या प्रमाणबद्धतेमुळेही संरक्षण यंत्रणा क्षीण होण्याची शक्यता कमी होते, कारण वस्तुमान-विशिष्ट चयापचय दरातील वाढीमुळे कर्करोग-कारक उत्परिवर्तनांच्या दरात वाढ होते.

Reduced Cancer Risk throughout the Animal Kingdom

 Genes (Basel). 2024 Jan 18;15(1):118. doi: 10.3390/genes15010118

From Churchill to Elephants: The Role of Protective Genes against Cancer

Annalisa Gazzellone 1, Eugenio Sangiorgi 1,*

Editor: Peixin Dong1

5. Reduced Cancer Risk throughout the Animal Kingdom

Apart from various animal models, the investigations into the cancer-protective effect mediated by genes in the animal kingdom have been explored starting from the observation that some very large animals, such as elephants and whales, with a very long lifespan, present a very low rate of cancer. However, this correlation is not perfect within the same species, such as in dogs, in which larger breeds are generally more prone to cancer development than smaller breeds. Conversely, in species of very small size, such as bats, they tend to be more cancer-resistant than mice, despite having similar sizes. Another interesting species in this respect is the naked mole-rat, which, in spite being a rodent of the size of a mouse, has an extremely long lifespan of up to 30–40 years and is extremely cancer-resistant. These studies aim to determine whether different species, particularly those with longer lifespans than humans, can provide valuable insights into the functioning of the major pathways involved in tumorigenesis, and how evolution solved the Peto’s paradox in those species.

Among the extensively studied animal models, elephants have garnered significant attention. This species exhibits an estimated cancer mortality of 4.81%, which is nearly half the observed mortality rate in humans, which ranges 

from 11% to 25% [71]. This disparity has been associated with elephants possessing 20 copies of the Tp53 gene, which differ in length and sequence content [72]. Notably, in the Loxodonta africana species, recent research has demonstrated that the 20 isoforms of the Tp53 gene feature distinct BOX-I Mdm2-binding motifs [73].

MDM2, an oncoprotein, primarily interacts with TP53, facilitating its degradation. This process ensures TP53 activation only when necessary or in response to cellular damage. The proposed mechanism behind the lower incidence of tumors in elephants revolves around the existence of diverse binding epitopes that interact with Mdm2. These distinct pools of Tp53 proteins result in an enhanced apoptotic response to DNA damage [73]. The variations in BOX-I sequences of Mdm2 hinder the interaction between Tp53 and Mdm2, thereby preventing Mdm2-mediated degradation of Tp53. As a result, Tp53 continues to fulfill its role as the guardian of the genome. Having multiple finely tuned copies of Tp53 prevents cells from attempting to repair irreparable DNA damage, thereby shifting the balance towards apoptosis. This multiple-copy configuration serves as an evolutionary fail-safe mechanism against the loss of a single gene copy, as can occur in humans.

Another species extensively scrutinized for low tumor incidence is the Greenland whale (Balaena mysticetus). 

This species boasts a remarkable lifespan exceeding 200 years and displays a lower tumor incidence despite its size, which entails a larger number of cells and significantly greater replication and repair mechanisms compared to humans.

In this long-lived species, the heightened expression of certain proteins involved in oncogenesis, such as Ercc1 and Pcna, has been observed, suggesting a potential protective role against tumors. Ercc1, an endonuclease involved in DNA damage repair, specifically addresses cross-links and mediates nucleotide excision repair [74]. Activating mutations in the Ercc1 gene have been identified in B. mysticetus [75], while in mice, inactivating mutations in this gene are associated with a higher incidence of tumors [76].

Furthermore, an elevated expression of the Pcna gene has been observed in Greenland whales [75]. This gene encodes a protein that plays a crucial role in supporting polymerase activity during DNA replication and repair processes [76].

The Pcna protein holds significant importance in maintaining the polymerase’s attachment to DNA, thus playing a fundamental role in DNA replication. In instances of DNA damage, this protein undergoes ubiquitination, triggering two DNA repair pathways: homologous recombination and nucleotide excision repair. The suggested mechanism behind the greater resistance to DNA damage and the subsequent lower incidence of tumors in Greenland whales involves the overexpression of the Pcna gene and, consequently, an increased production of the protein.

Similar patterns have been observed in other animal species where the expression levels of Pcna in specific organs show a close correlation with cell proliferation. For instance, in the livers of rats, lower levels of the Pcna protein have been linked to decreased levels of cell regeneration [77].

The naked mole-rat serves as a fascinating example for several reasons [78]. Firstly, it is a very small animal with an extraordinarily long lifespan for its size. Secondly, its longevity likely derives also from an incredible resistance to cancer, mediated by a unique mechanism. While elephants and whales exploit some well-known genes for their cancer-resistant traits, Tp53 and Ercc1, both directly involved in DNA repair, apoptosis, and essential cell-cycle decisions, the scientific perspective shifts significantly when examining the naked mole-rat.

The molecule responsible for this unique resistance is a high molecular weight hyaluronan, a glycosaminoglycan (the primary non-protein molecule in the extracellular matrix), secreted by fibroblasts and produced abundantly by hyaluronan synthase 2 (Has2) during postnatal life [79]. The Has2 protein found in the naked mole-rat differs from the mouse and human sequences, due to the substitution of two highly conserved asparagines with two serines. These alterations occur within the catalytic region, resulting in the enzyme from the naked mole-rat being highly processive and producing very high molecular weight

 hyaluronan.

Fibroblasts from naked mole-rats exhibit early contact inhibition, halting their growth at significantly lower densities. This mechanism is likely mediated by hyaluronan within the extracellular matrix, which directly interacts with Cd44 on the cell surface. This interaction induces early contact inhibition through p16INK4a, resulting in reduced cell proliferation, reduced hyperplasia and metastatic potential, and, on a systemic level, reduced inflammation. Additionally, it acts as an antioxidant, decreasing damage from reactive oxygen species to DNA and proteins, 

and makes cells more prone to apoptosis following 

the loss of tumor-suppressor genes [80,81].

The final confirmation that hyaluronan mediated these effects was achieved by increasing the lifespan of mice and enhancing their cancer resistance beyond that of control mice after expressing the naked mole-rat version of Hsa2. The increased expression of hyaluronan not only extended lifespan but also ensured a healthier one in mice [82] (Figure 4

Figure 4

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Different pathways play a role in protecting animals against tumors. In elephants, the gene Tp53 undergoes amplification, increasing up to 20 copies. The finely regulated multiple copies of this gene, activated by DNA damage, prevent the transformation of cells with significant DNA damage into cancerous cells by 

inducing apoptosis. Similarly, in whales, a comparable effect is achieved through the overexpression of the ERCC1 protein. This overexpression enhances the whales’ capability to repair DNA, contributing to a heightened defense against cancer. Conversely, the naked mole-rat utilizes a completely distinct mechanism for tumor protection. These rodents synthesize an exceptionally large hyaluronan molecule, which induces early contact inhibition in fibroblasts. This process leads to reduced cell proliferation, diminished hyperplasia, decreased inflammation, and a lowered potential for metastasis. Up and down arrows stand for “increased” or “decreased”