Low cancer rates in nonhuman primates

EUGENE M. MCCARTHY, PHD GENETICS, ΦΒΚ

Humans differ markedly from nonhuman primates with respect to susceptibility to cancer. Thus, Puente et al. (2006) note that the the incidence of cancer in the latter is very low. They go on to say that

This fact is especially evident for epithelial neoplasms^† such as breast, prostate or lung carcinomas, which are responsible for more than 20% of human deaths but whose incidence in great apes is less than 2%.^‡

† Note that while all cancers are neoplasms, not all neoplasms are cancerous. Neoplasms are simply new and abnormal growths of tissue in some part of the body, whereas the term cancer is nearly equivalent to the term malignant tumor. Most neoplasms are not malignant.

‡ These authors cite: Beniashvili (1989), McClure (1973), Seibold and Wolf (1973), Varki (2000), and Waters et al. (1998, p. 64).

And this difference is not an artifact of small sample sizes. Beniashvili (1989, p. 423) comments that “Although tumors occur commonly in man, they have been rather infrequently reported in monkeys and apes, despite the fact that many thousands have been maintained in zoological gardens, primate centers, other research centers, and poliomyelitis vaccine production laboratories.”

Varki (2000) confirms these findings:

Another surprising difference [between humans and chimpanzees] appears to be in the frequency of the most common human cancers, which are epithelial neoplasms such as carcinomas of the breast, ovary, lung, stomach, colon, pancreas, and prostate. Whereas these cancers cause >20% of deaths in modern human populations (Parker et al. 1997), an extensive literature suggests that the cancer incidence rates for the nonhuman primates is only ~2%-4% and seems even lower in the great apes (McClure 1973; Seibold and Wolf 1973; Schmidt 1978; Beniashvili 1989; Scott 1992). Although the numbers of well-documented autopsied on great apes are relatively small (in the hundreds), several factors suggest that this apparent difference is not due to ascertainment bias.”

These rates of incidence do not seem to be explicable in terms of the shorter lifespans of nonhuman primates in comparison with humans. Thus, with regard to prostate cancer, Waters et al. (1998) comment that, "in the last decade, large numbers of elderly male nonhuman primates (last 10% of estimated lifespan) have been carefully evaluated; the absence of prostatic lesions confirms that prostate carcinoma is almost nonexistent in nonhuman primates.” And yet, in many regions of the world, prostate cancer is the most commonly diagnosed cancer among men (Center et al. 2012). Waters et al. go on to say nonhuman primates have very low rates of even benign prostatic lesions.

In summary, nonhuman primates do not appear to be a suitable experimental or spontaneous model for prostatic carcinoma. However, the relative absence of disease could make them a useful negative model with the potential to identify protective factors that could explain the relative resistance of nonhuman primates to BPH [i.e., benign prostatic hyperplasia] or prostatic carcinoma.

Siebold and Wolf (1973, p. 536, Table 2) reported on 1066 necropsies of nonhuman primates. Among these were 52 chimpanzees in which 6 tumors were observed, none of which were malignant. In the whole study, among all animals, they found only 24 tumors of any kind, just 4 of which were malignant, corresponding to a cancer incidence of 0.38 percent (compare this with the human death rate from malignant epithelial tumors alone of more than 20%). Stanford (2018) states that “Some of the most prevalent human diseases that occur later in life, such as most cancers, are barely known in chimpanzees.”

O'Gara and Adamson (1972, p. 194) emphasize the relative invulnerability of non-human primates to chemicals that reliably produce cancer in humans:

Pfeiffer and Allen made a heroic attempt to induce neoplasia in rhesus monkeys with polycyclic hybrocarbons and estrogens.…Carcinogenic polycyclic hydrocarbons were injected or implanted subcutaneously, painted on the skin, or dusted as crystals into the peritoneal cavity; some was sewed into omental pockets or placed directly on the uterus; and pellets of carcinogens were implanted in the myometrium, in the cervix, in the submucosa of the vagina, in the mammary glands or at other sites. Methylcholanthrene^‡ was also given intravenously and orally in large doses. Out of 50 monkeys, some of which were treated over a period of 11 years, none developed cancer although 12 monkeys survived 3 years of treatment, and 5 survived for 5 to 11 years.

‡ In humans methylcholanthrene is a highly carcinogenic mutagen.

‡ Diethylnitrosamine (DENA) is a well-known hepatocarcinogenic agent present in tobacco smoke, water, cured and fried meats, cheddar cheese, agricultural chemicals, cosmetics and pharmaceutical products (Brown 1999, Reh et al. 1996, Sullivan et al. 1991).

Other carcinogens^* tested in the National Cancer Institute studies cited by O'Gara and Adamson (1972, pp. 216-230) included:

aflatoxin, orally and by intraperitoneal injections;
cycasin, orally;
2-fluorenyl acetamide, orally;
2-,7-fluorenyl acetamide, orally;
N-OH fluorenyl acetamide, orally and by injection;
N,N¹-dimethl-p-phenylazoaniline (DAB), orally;
N,N¹-dimethyl-p-(m-tolylazo) aniline (3' Me DAB), orally;
ethyl carbamate (urethan), orally 5x weekly, half of these subjects also received 500r of X-ray irradiation;
procarbazine hydrochloride (N-isopropyl-α(2-methylhydrazine)-p-toluamide, hydrochloride), orally or by injection, produced one case of a acute myeloid leukemia;
3-methylcholanthrene, orally or by injection; injections induced fibrosarcoma in three tree shrews (Tupaia glis);
3,4,9,10-dibenzopyrene, orally or by injection.

* No cancers were induced by these chemicals, except, as indicated, in one monkey and a few tree shrews. O'Gara and Adamson (1972, p. 216) state that "These compounds were all powerful carcinogens in mice and rats."

Indeed, O'Gara and Adamson (ibid., p. 216) say that over 500 monkeys "treated by various routes with carcinogenic chemicals at maximum doses" by researchers at the National Cancer Institute did not develop tumors, except in the case of those individuals treated with diethylnitrosamine (DENA), which did induce hepatomas and hepatic cell carcinomas in about 50 monkeys. But all the other chemicals did not (ibid., see pp. 216-230), except in some tree shrews (Tupaia).^‡

The rarity of cancer in non-human primates has long been recognized. Ratcliffe (1933) reported that, of 971 primates examined at the Philadelphia Zoo, only eight had tumors. This is a very low rate (0.82%). Moreover, the actual rate of cancer among these animals must have been even lower since most of those tumors would have been expected to be benign.

Ruch (1959, p. 531, citing Ratcliffe 1940) stated that at the Philadelphia Zoo from 1901-1939, 4 of 95 the rhesus macaques (Macaca mulatta) had tumors; 7 of 448 of the other Old World monkeys in their holdings (“other Cercopithecidae”) and 4 of 407 “other primates.” These figures translate to incidences of 4.2%, 1.6% and 0.98%, respectively. Again, it was not indicated whether the tumors were benign or malignant, so the incidence actual cancer would have been lower. And papers read for the present review strongly suggest that the incidence of cancer in great apes is even lower than that seen in other types of non-human primates.

In his paper An Examination of Chimpanzee Use in Human Cancer Research , Bailey (2009) goes so far as to say that his review of the literature “determined that chimpanzees have scarcely been used in any form of cancer research and that chimpanzee tumours are both rare and biologically different from human cancers.” Bailey appears to be biased against the use of chimpanzees in biomedical research, but his methods do seem thorough. One passage, in particular (Bailey, pp. 400-401), suggests how scant the observations of cancer in chimpanzees truly are.

Fourteen papers were basic reports [that is, case reports, as opposed to surveys] of tumours in chimpanzees, with no direct relevance to human cancer. Seven of these papers reported malignant tumours, five described benign tumours, and two papers described tumours that can be of either type. The tumours described in these fourteen papers comprised: a report of a leiomyoma and an endometrial stromal tumour (17); pulmonary myeloproliferative malignant neoplasms (18); ovarian Sertoli-Leydig cell tumour (arrhenoblastoma) (19) and fibrothecomas (20); a nasopharyngeal carcinoma (21); malignant melanoma^* (22); hepatocellular carcinoma (23) associated with hepatitis C virus (24) or Schistosoma mansoni infection (25); renal carcinoma (26); anaplastic large cell lymphoma (27); adenoma of the gallbladder (28); focal nodular hyperplasia and myelolipoma (23); gastrointestinal stromal tumour (29); and nevus lipomatosus cutaneous superficialis (30).

These reports, which were deemed worthy of inclusion in peer-reviewed journals because they were unprecedented accounts of different tumour types in chimpanzees, illustrate their rarity. This is openly acknowledged in the abstracts — for example, Porter et al. (23) state, “Hepatic neoplasia is rare in chimpanzees. Only four hepatic neoplasms have been reported in chimpanzees, three of which were associated with viral hepatitis.

* Not having previously been able to find any report whatsoever mentioning a case of melanoma in a chimpanzee, I tried to obtain the French-language paper cited by Bailey (Barriere et al. 1984). However, the journal in which it appeared, Annales de Dermatologie et de Venereologie seems not to be available in North America. So I contacted Bailey to see if he could send me the paper, but he couldn't find his copy. So this single report, if it does correctly report a rare case of melanoma in a chimpanzee, is virtually unavailable.

In a recent paper Varki and Varki (2015), say that among the various differences between humans and chimpanzees in disease incidence,

one that has been emphasized in multiple reports is the rarity of occurrence of common human carcinomas in captive chimpanzees. Earlier surveys reporting on disease profiles and causes of death in captive chimpanzees from US facilities noted the rarity of these cancers [23–27]. A more recent thorough analysis [they cite Brown et al. 2009] listed all neoplasms documented at two long-standing major US facilities from their inception many decades ago, through mid-2008. While the denominator (the total number of chimpanzees and life years at risk) was not made clear, there were only nine spontaneously arising epithelial malignancies reported over these many decades of observations of colonies that measured in the many hundreds. Moreover, even these cancers did not arise in the usual sites observed in humans, and were: one kidney carcinoma, one malignant carcinoma of the uterus, one basal-squamous carcinoma, one thyroid carcinoma, one adenocarcinoma of the parotid salivary gland, one nasopharyngeal carcinoma and three hepatocellular carcinomas (HCCs). There were a few additional cases of HCCs that were associated with experimental chronic hepatitis infection. No carcinomas of colon, breast, lung, prostate, stomach, pancreas or ovary were reported in this cohort.

Finally, it can be noted that the impression given by the papers read for this survey is that there is a much higher tendency for tumors to regress and metastasize in non-human primates than in humans. Thus, it was early recognized (Ruch 1959, pp. 537-540) that in efforts with carcinogens to induce tumors in nonhuman primates, even when tumors were successfully induced, and even they began to invade surrounding tissue, they never metastasized and nearly always regressed, which is certainly not the typical observation with invasive tumors in human beings. Ruch (1959) quantified this impression. He states (p. 364) that up to the date of his book's publication, metastasis had not been experimentally produced in monkeys and that in monkeys only about five percent of spontaneous tumors had ever metastasized, and that moreover most had regressed.

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