Occurrence Of Spontaneous Tumors Research Articles

Exploring the contrasts: in-depth analysis of human and canine mammary tumors - discoveries at the frontier.

We have examined genomic and transcriptomic abnormalities in human and canine samples to evaluate the canine model's validity for breast cancer research, emphasizing similarities and differences. Both species commonly utilize serum tumor markers and noncoding microRNAs. Immunohistochemistry and immunocytochemistry were employed to illustrate and compare results based on histological diagnoses. In addition to these factors, similarities exist in spontaneous tumor occurrence, age of onset, hormonal influences, and disease progression, including tumor size, clinical stage, and lymph node involvement. Molecular traits such as hormone receptor status, Epidermal Growth Factor Receptor (EGFR), and proliferation markers (Ki67) further endorse the canine model's utility in breast cancer studies. The advancement of technologies facilitates the identification of new cancer-associated molecules, both coding and non-coding genes, underscoring their potential as prognostic/diagnostic biomarkers and therapeutic targets.

Abstract 2339: Exploration of multiple immunotherapy modalities in ostesarcoma

Abstract Osteosarcoma (OS) is the most common primary bone malignancy affecting long bones in children and the third most frequent in adults in the United States. It is highly invasive and metastatic. The survival rates over the last 20 years are unchanged. Therefore, it is essential to develop novel, targeted therapeutic approaches to treat OS. In pursuit of that goal, novel models are needed. Due to the high similarity in cancer genetics, the spontaneous occurrence of tumors, and the presence of an intact immune system, dogs are deemed an excellent cancer immunotherapy model. OS is also the most common malignant bone tumor (80%) in dogs. Monotherapies like oncolytic viruses and immune checkpoint inhibitors have been shown to be insufficient for effective cancer treatment. Therefore, we propose a combination of immune checkpoint inhibition and oncolytic virotherapy to target osteosarcoma tumor cells. In this combined therapy, the oncolytic virus will serve to both stimulate an inflammatory response and transmit the checkpoint inhibitor, which in turn will block PD-1-directed down-regulation of T cells, allowing the adaptive immune system to respond better to tumors. In order to evaluate this approach in the canine model, we have developed an oncolytic virus (CAV2-AU-M2) based on canine adenovirus type 2 and armed with an immune checkpoint inhibitor, an anti-canine PD1 single domain camelid antibody (sdAb). Four canine osteosarcoma cell lines, D17, D22, MCKOS, and CF11, were cultured in two-dimensional (2D) and three-dimensional (3D) cultures and were infected with CAV2-AU-M2 to analyze the infective and lytic effects of the virus. CAV2-AU-M2 infected and lysed the cells in 2D. The virus also produced anti-PD1 sdAb upon infecting the cells. Similarly, results were evident in 3D cultures. The virus infected the spheroids in the outer layers on Day 4 and slowly diffused towards the core in 7 days. The spheroids infected started showing some cell death on day 4, which progressed significantly by Day 7. This approach to oncolytic virotherapy makes the tumor more visible to the immune system and abrogates tumor-induced immune suppression. Citation Format: Aliaa A. Ismail, Daniel J. Patton, Theresa A. Higgins, Maninder Sandey, Bruce F. Smith, Payal Agarwal. Exploration of multiple immunotherapy modalities in ostesarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2339.

Cancer in Amphibia, a rare phenomenon?

Compared to other animals, the spontaneous occurrence of tumors in wild amphibians is relatively rare, generally limited to specific populations or species. The number of reports of spontaneous tumors in amphibians known up to 1986 was 491 cases in anurans and about 253 cases in urodeles. Similarly, there have been many, unsuccessful attempts to chemically or biologically induce tumors in amphibians. With these considerations, it is inevitable to wonder: do urodeles and anurans have an inherent resistance to cancer? Here, we review the spontaneous and induced occurrence of tumors in amphibians in a timeline, as well as failed attempts to induce tumors in these amphibians. Indeed, recent studies seem to indicate that there is a relationship between regeneration and cancerbecause regenerating tissues seem to resist tumorigenesis, as opposed to nonregenerative tissues of the same amphibian models. Although the mechanisms that allow regenerating tissues to resist tumorigenesis have not been elucidated, it is worth to note that, in addition to the apparent relationship between regeneration and cancer, amphibians possess characteristics that could contribute to their ability to resist the development of neoplastic events. The implications of these features in cancer susceptibility are discussed.

Evaluation of the Occurrence of Spontaneous Tumours in Young Dogs

Evaluation of the Occurrence of Spontaneous Tumours in Young Dogs

Tumours in 177 pet hamsters.

Even though tumours are considered to occur frequently in pet hamsters, there is only a small number of scientific reports in current literature. Pathological reports from 177 hamsters were evaluated. Of these, 78 were male and 75 were female. Median age of affected hamsters was 12 months (range 2-34). Integumental tumours were the most common neoplasms (62%, 109/177). As far as species was known, the number of Syrian hamsters (52%, 30/58) affected by tumours seemed to be lower than the number of affected dwarf hamsters (85%, 47/55). Tumours of the hematopoietic system were the second most frequently neoplasms (17%, 30/177). Relative number of neoplasms of the endocrine system, tumours of the digestive system (1.7%, 3/177) and other tumours (4%, 7/177 each) was low. The majority of integumental tumours were epithelial (66%; 91/126). This study aimed to analyze data from veterinary surgeries and pathological institutes about the occurrence of spontaneous tumours in Syrian hamsters and dwarf hamsters to give information about the frequency of tumours, prognosis and survival time. This is the first study about tumours in pet hamsters in Germany so far.

Dermal Delivery of Constructs Encoding Cre Recombinase to Induce Skin Tumors in PtenLoxP/LoxP;BrafCA/+ Mice.

Current genetically-engineered mouse melanoma models are often based on Tyr::CreERT2-controlled MAPK pathway activation by the BRAFV600E mutation and PI3K pathway activation by loss of PTEN. The major drawback of these models is the occurrence of spontaneous tumors caused by leakiness of the Tyr::CreERT2 system, hampering long-term experiments. To address this problem, we investigated several approaches to optimally provide local delivery of Cre recombinase, including injection of lentiviral particles, DNA tattoo administration and particle-mediated gene transfer, to induce melanomas in PtenLoxP/LoxP;BrafCA/+ mice lacking the Tyr::CreERT2 allele. We found that dermal delivery of the Cre recombinase gene under the control of a non-specific CAG promoter induced the formation of melanomas, but also keratoacanthoma and squamous cell carcinomas. Delivery of Cre recombinase DNA under the control of melanocyte-specific promoters in PtenLoxP/LoxP;BrafCA/+ mice resulted in sole melanoma induction. The growth rate and histological features of the induced tumors were similar to 4-hydroxytamoxifen-induced tumors in Tyr::CreERT2;PtenLoxP/LoxP;BrafCA/+ mice, while the onset of spontaneous tumors was prevented completely. These novel induction methods will allow long-term experiments in mouse models of skin malignancies.

Vaccination with ErbB-2 peptides prevents cancer stem cell expansion and suppresses the development of spontaneous tumors in MMTV-PyMT transgenic mice.

ErbB-2 has been implicated as a target for cancer-initiating cells in breast and other cancers. ErbB-2-directed peptide vaccines have been shown to be effective in prevention of spontaneous tumorigenesis of breast in neu transgenic mouse model, and cellular immunity is proposed as a mechanism for the anti-tumor efficacy. However, there has been no explanation as to how immunity suppresses tumorigenesis from the early stage carcinogenesis, when ErbB-2 expression in breast is low. Here, we investigated a peptide-based vaccine, which consists of two MHC class II epitopes derived from murine ErbB-2, to prevent the occurrence of spontaneous tumors in breast and assess immune impact on breast cancer stem cells. Female MMTV-PyMT transgenic mice were immunized with either ErbB-2 peptide vaccine, or a peptide from tetanus toxoid, or PBS in immune adjuvant. ErbB-2 peptides vaccine completely suppressed spontaneous breast tumors, and the efficacy was correlated with antigen-specific T-cell and antibody responses. In addition, immune serum from the mice of ErbB-2 vaccine group had an inhibitory effect on mammosphere-forming capacity and signaling through ErbB-2 and downstream Akt pathway in ErbB-2 overexpressing mouse mammary cancer cells. We provide evidence that multi-epitope class II peptides vaccine suppresses tumorigenesis of breast potentially by inhibiting the growth of cancer stem cells. We also suggest that a strategy of inducing strong immune responses using multi-epitope ErbB-2-directed helper vaccine might be useful in preventing breast cancer recurrence.

A key role for neuropeptide Y in lifespan extension and cancer suppression via dietary restriction

Knowledge of genes essential for the life-extending effect of dietary restriction (DR) in mammals is incomplete. In this study, we found that neuropeptide Y (Npy), which mediates physiological adaptations to energy deficits, is an essential link between DR and longevity in mice. The lifespan-prolonging effect of lifelong 30% DR was attenuated in Npy-null mice, as was the effect on the occurrence of spontaneous tumors and oxidative stress responses in comparison to wild-type mice. In contrast, the physiological processes activated during adaptation to DR, including inhibition of anabolic signaling molecules (insulin and insulin-like growth factor-1), modulation of adipokine and corticosterone levels, and preferential fatty acid oxidation, were unaffected by the absence of Npy. These results suggest a key role for Npy in mediating the effects of DR. We also provide evidence that most of the physiological adaptations to DR could be achieved in mice without Npy.

Occurrence of Spontaneous Tumors in the Central Nervous System (CNS) of F344 and SD Rats

In order to accurately assess the carcinogenicity of chemicals with regard to rare tumors such as rat CNS tumors, sufficient information about spontaneous tumors are very important. This paper presents the data on the type, incidence and detected age of CNS tumors in F344/DuCrlCrlj (a total of 1363 males and 1363 females) and Crl:CD(SD) rats (a total of 1650 males and 1705 females) collected from in-house background data-collection studies and control groups of carcinogenicity studies at our laboratory, together with those previously reported in F344 and SD rats. The present data on F344/DuCrlCrlj rats (F344 rats) and Crl:CD(SD) rats (SD rats) clarified the following. (1) The incidences of all CNS tumors observed in F344 rats were less than 1%. (2) The incidences of malignant astrocytoma and granular cell tumor were higher in male SD rats than in female SD rats. (3) The incidences of astrocytoma and granular cell tumor were higher in SD rats than in F344 rats. (4) Among astrocytoma, oligodendroglioma and granular cell tumor, oligodendroglioma was detected at the youngest age, followed by astrocytoma, and ultimately, granular cell tumor developed in both strains. The incidences observed in our study were almost consistent with those previously reported in F344 and SD rats.

Spontaneous Tumors in the Uterus, Testis and Other Organs of F1 Hybrids between Donryu and F344 Rats.

In order to assess the effects of genetic factors on spontaneous tumor development in various organs/tissues, especially the reproductive organs of Donryu and F344 rats, F1 hybrids between these two strains were investigated. Litters were obtained by mating virgin Donryu or F344 females with F344 or Donryu males, respectively. They were weaned at 4 weeks of age and divided into two hybrid groups: Group A, (Donryu female × F344 male) F1 (male n=49, female n=48) and group B, (F344 female × Donryu male) F1 (male n=53, female n=56). These two groups of F1 hybrids were observed with their parents (Donryu male n=19, female n=30; F344 male n=21, female n=29) until 120 weeks of age. The incidences of persistent estrus in both F1 groups from 8 to 12 months of age were in between those for their Donryu and F344 mothers, being slightly higher in group A than in group B. They increased thereafter and reached about 90% and 80% at 18 months of age in groups A and B, respectively. In females of group A, the incidences of endometrial hyperplasias and adenocarcinomas were comparable with those in the Donryu strain, and higher than those in group B, whose values were in turn elevated as compared to their F344 mothers. In contrast, endometrial stromal polyps and Leydig cell tumors of the testes were observed with similar incidences in both hybrids as well as F344 rats, but at markedly lower levels in the Donryu strain. The frequency of mononuclear cell leukemias was very low in both F1 groups of each sex. Various tumors were also observed in many other organs/tissues such as the pituitary, thyroid, pancreas, adrenals, mammary and prostate glands and their incidences were relatively high in both groups A and B, but their variation between the F1 groups was small. These results indicate that development of uterine endometrial hyperplasias/carcinomas in F1 hybrids might be related to hormonal conditions depending on the genetic background of the mothers, but other tumors are considered to be influenced by other factors. The effects of genetic background on the occurrence of spontaneous tumors in hybrids are very complex and differ not only with the site but also the tumor types.

Adaptive role of caloric intake on the degenerative disease processes.

Carcinogenicity and aging are characterized by a set of complex endpoints, which appear as a series of molecular events. Many of these events can be modified by caloric intake. Since most of these processes determine an organism's ability to cope with various environmental stressors, it is not surprising that a relationship (in the presence of a constant nutrient density) exists between caloric intake and time-to-tumor and/or life span. Our studies have clearly shown that generally, the greater the caloric intake, the greater the body weight, the higher the incidence of spontaneous tumor occurrence, the greater the susceptibility to chemical carcinogens, and the shorter the life span. It is also recognized that variables other than body weight influence the life span and carcinogenesis. We have focused our attention on the questions of how and to what extent caloric intake modifies those homeostatic processes believed to be critical in determining the ability of an organism to cope with endogenous and exogenous stresses such as chemical, physical, and biological carcinogens. The response of an organism to its environment can be divided into four categories--physiological, metabolic, molecular, and cellular. We have found that, from a physiological perspective, decreasing caloric intake causes body temperature in rodents to be decreased by 0.5 to 1.8 degrees C and water consumption to be increased by 80%, as is running activity. However, metabolic output per gram of lean body mass is not altered. Reproductive capacity declines, whereas the ECG waveform is preserved as caloric intake decreases. Alterations in these and other physiological functions suggests that energy intake serves as a signal to up-regulate or down-regulate functions related to the flight-or-fight response observed in placental mammals. A number of key metabolic pathways are altered as a function of lowered caloric intake, even though the rate of food consumption per gram of lean body mass remains steady during body weight decreases caused by decreasing caloric intake. Pharmacological compartmentalization, however, is altered. As caloric intake declines, changes occur in the expression of a number of drug-metabolizing enzymes, with the most striking effect seen in sex-specific growth hormones and liver-dependent phase I and phase II enzymes. Additionally, oxidative stress (free-radical and mediated damage to macromolecules) appears to decrease as a function of reduced caloric intake. A number of molecular processes also change with changes in energy consumption. Our studies have shown that, regardless of the source and nature of DNA damage, DNA repair is better preserved and/or enhanced when caloric consumption decreases. In addition, the fidelity of DNA replication increases and oncogene expression is stabilized, P53 gene expression is increased, and apoptosis is elevated by up to 500% with decreased caloric intake. At the cellular level, cell proliferation is decreased in direct proportion to lower energy intake in some but not all tissues. Studies have also shown an enhancement in immune capacity, changes in IGF1, and accelerated rates of wound healing proportionate to declines in energy consumption. Our most recent findings, however, have shown that the benefits associated with decreases in caloric intake only occur in the presence of sufficient nutrient quality and density. In the absence of proper nutrition, however, sensitivity to carcinogens and toxic substances appears to be enhanced. These findings are supported by independent studies. These observations have led us to conclude that, in certain organisms, when caloric intake is decreased, there is an up-regulation of those processes that modulate the responses to a wide range of environmental stressors. This response allows for a better survival rate and a down-regulation of reproductive activity. It is our belief that, during periods of environmental stress, these systems may be essential to perpetu

Tests for a trend in proportion based on mixtures of beta distributions incorporating historical controls

Carcinogen bioassay involves the exposure of laboratory animals to one or more levels of the test substance and an evaluation of the tumor occurrence rates in the treated groups relative to those in the unexposed controls. The historical control groups obtained from other similar studies also provide information concerning the rate of spontaneous tumor occurrence and may be useful in analyzing the results of the current experiment. This is especially relevant when the tumor is of rare type where the toxicologist places great significance on its occurrence in a treatment group. Under the assumption that historical control and concurrent control tumor rates are identically distributed, several authors have investigated the problem of statistical incorporation of the historical data into the current control group while testing for an increasing trend in the proportions across the treatment groups. Often this is not the case, as the historical data are gathered from studies subject to profound sources of variation, such as animal age, animal body weight, and pathologists which occur even under the same protocol. In this article we relax this assumption and develop locally most powerful tests for a trend in binomial response data by using the mixtures of beta distributions as models to accommodate the extra-binomial variation in the historical controls. The asymptotic distributions of the test statistics are obtained under the null hypothesis of no trend in proportions and also for a sequence of Pitman alternatives converging to the null hypothesis. Using these results, the application of the tests with the experimental as well as hypothetical data sets is demonstrated. The robustness of these tests under small perturbations in the historical control data is studied. The study shows that the tests based on the mixtures of beta distributions are robust in the sense that their p-values do not fluctuate under small perturbations in the historical data, unlike some of the existing test procedures. Thus while incorporating the historical data, the mixture distributions are more appropriate than the existing procedures for modelling the variation in the historical controls. Copyright © 1999 John Wiley & Sons, Ltd.

Incidence of Spontaneous Tumors in a Group of Retired Breeder Female Brown Norway Rats<xref ref-type="fn" rid="FN2">2</xref>

A group of 80 female retired breeder inbred Brown Norway (BN) rats with recorded breeding histories was followed for 150 weeks with regard to spontaneous occurrence of tumors. The median survival time of the whole group was 134 weeks. Ninety tumors (42 benign tumors, 23 sarcomas, and 25 carcinomas) were found in 64 animals. Compared with previous findings on virgin female BN rats, the retired breeders used in the present study had a strikingly higher incidence (34%) of tumors of the genital system but a lower incidence (4%) of breast tumors. The breeding histories revealed no relationship between the recorded number of litters, number of newborns, age of the mother at the time of her first litter, preweanling mortality, and the occurrence of cancer or survival in general. Although all animals were kept under identical environmental conditions, animals born in the period July-December appeared to have a lower incidence of utero-vaginal tumors than animals born in the first half of the year. The growth rates of 32 tumors inoculated into syngeneic rats were monitored for 26 weeks. They did not correlate with the histopathologic characteristics of the specific tumor. Malignant or benign tumors showed the same growth variability.

Occurrence of Spontaneous Tumors in the Germfree F344 Rat 2

The incidence of spontaneously occurring neoplasms was observed over 10 years in a colony of germfree F344 rats (78 males and 102 females) representing 10 generations of inbredding. Leukemia was the most common neoplasm (25.6% of males, 36% of females) followed by mammary tumors (11.5% of males, 19.6% of females). Various other tumors developed in 9% of the males and 5% of the females. The overall incidence of spontaneous tumors was comparable to that reported for conventional rats of different strains. This was particularly true of leukemia for which the most data were available. However, for unknown reasons, significantly fewer solid tumors were observed in germfree than in conventional male rats.

Contraceptive steroid toxicology in the Beagle dog and its relevance to human carcinogenicity

Problems associated with the use of the Beagle dog in chronic toxicological studies of contraceptive steroids are described. A short review is presented on the occurrence of spontaneous tumours in dogs and in bitches of various breeds. The current status of knowledge of canine reproductive hormones and endocrinology is outlined, together with effects of contraceptive steroids. The pathology and histological classification of spontaneous and induced mammary neoplasia in the dog is discussed and compared with breast cancer in women. A series of recommendations are included for future research in this field which it is hoped may resolve some of the outstanding issues and lead to a more suitable toxicological model for contraceptive steroids.

Guinea pigs and carcinogens.

The reaction of guinea pig skin to topical and subcutaneous administration of four carcinogens administered in different dosages to newborn and adult animals, has been investigated histologically and histochemically. The transplantability of the sarcomas produced, and the occurrence of spontaneous tumours in the strain used, was studied too. The guinea pig was resistant to topical carcinogen treatment, but large doses administered during a long period did induce tumorigenesis. The resulting tumours were all fibrosarcomas. The newborn animals were as resistant as adults. The transplantation of the tumours was successfull, but the percentage of positive “takes” was small. A single dermal tumour occurred spontaneously in the control group consisting of 500 animals.

新しく亜系として確立された乳因子のないC3HeB/Osマウスの自然発生腫瘍について

新しく亜系として確立された乳因子のないC3HeB/Osマウスの自然発生腫瘍について

Transplantable Lymphosarcomata of the Mesenteric Lymph Nodes of Rats

More than a decade ago F. D. Bullock and M. R. Curtis (1) published a descriptive article on 521 primary spontaneous tumors which had been observed during the first ten years of existence of their rat colony at the Crocker Institute of Cancer Research, Columbia University. Of the 91 of these tumors which involved the cecum or ileocolic mesentery of the cecal region, 13 (14.3 per cent) probably originated in the cecal wall. Morphologically, 10 of these were sarcomata of the spindle-cell and mixed-cell type, 2 fibromata, and 1 adenocarcinoma. The other 78 (85.7 per cent) apparently arose in the lymph nodes of the ileocolic mesentery near the junction of the ileum, cecum and colon, and were of the lymphosarcoma type. The original description of these tumors (1) is equally applicable to the 220 which have since been observed in the animals of this colony. The descriptive study was followed by an analysis of the population data on the occurrence of spontaneous tumors in this same rat colony. This analysis (2) showed that of the deep-seated tumors, lymphosarcoma of the mesenteric lymph nodes was exceeded in frequency only by tumors of the thymic region and that neither type of neoplasm was distributed at random in the population, the former being most frequent in the Fischer strain and the latter confined to the Copenhagen strain, in which lymphosarcoma of the mesenteric lymph nodes had never been observed. The average age at autopsy of the bearers of the lymphosarcoma was 13.7 months; the bearers of the thymic tumors lived to an average age of 25.7 months. The rats of the Fischer and Copenhagen strains had average life spans, respectively, of 11 and 17.9 months.

Transplantable Carcinoma of the Rat Breast

In comparison to the incidence in the mouse, mammary cancer in the rat is uncommon. Curtis, Bullock and Dunning analyzed the data on the occurrence of spontaneous tumors in 392 of 31,868 autopsied rats of a pedigreed colony maintained in the Department of Cancer Research of Columbia University. In addition to 65 benign mammary tumors and 2 adenofibromata with sarcoma, keratinizing cystadenocarcinoma of the breast was observed in 2 (0.02 per cent) of 8,956 animals in the general population over the minimum tumor age. The tumor bearers were females of the Fischer and Marshall strains. Bryan, Klinck and Wolfe described an Albany strain of rats with a high incidence of breast tumors. Of 51 females, 25 had fibroadenoma or fibroma, and 1, approximately seventeen months of age, an adenocarcinoma with foci of squamous metaplasia and sarcoma. Dunning, Curtis and Bullock found 2 carcinosarcomata, consisting of adenocarcinoma and sarcoma, in a series of 778 tumors in rats produced subcutaneously with benzpyrene dissolved in paraffin. The carcinomatous elements in these tumors were in all probability of mammary origin and attributable to the action of the carcinogenic agent. Bagg and Hagopian succeeded in producing breast cancer in 4 female Wistar rats at the age of seventeen to twenty-eight months by rapid breeding and prevention of suckling. The identical experimental method gave rise to mammary fibroadenoma and adenoma or uterine leiomyoma in other animals. Tumor growth was associated with alterations in the adrenal and pituitary gland, indicating a basic disturbance in hormonal balance. Cancer was not transplantable in contrast to the successful transfer of the benign growths.

Hemoglobin Levels in Various Degrees of Susceptibility to Spontaneous Tumors

In 1907 (1), Tyzzer clearly emphasized the probable role of heredity in the origin of tumors in mice. The advances made since that time, both in the genetic investigation of the spontaneous tumor and in the study of the transplantable tumor rest largely upon his interest and work. In his 1907 paper, Tyzzer wrote: “Are the races of mice which are susceptible to the inoculable tumors more liable to spontaneous tumors than are the races which are insusceptible? Since heredity is so important a factor in the development of the inoculable tumors, its influence should not be disregarded in the occurrence of spontaneous tumors.” He further emphasized the value of selection in the establishment of uniform strains of mice. Whether the tendency to the frequent development of tumors is based on one general or on various specific “tumor characters” was a question that he considered. “The occurrence of ‘cell rests’ or misplaced tissue,” he states, “may possibly have some relation to the inherited tumor character,” but the tumor character according to Mendel's law cannot be a dominant one. Tyzzer then discussed the possibility of a single recessive character and pointed out the possibility that the development of a tumor may depend upon a combination of several inherited characters, rather than upon the presence of a single character. He thus anticipated the theory of multiple factors which plays such an important role in more recent discussions on the genetic nature of tumor susceptibility. According to Tyzzer, coat color had apparently no influence on tumor incidence, since mice of any color combination may develop spontaneous tumors. Tyzzer's conclusion at that time was to the effect that the results already obtained were not sufficiently numerous to prove or disprove that the development of a tumor is dependent upon the presence of an inherited character; although the data obtained may appear to favor this view. “It seems possible by certain lines of experimental breeding, with the principles of Mendel's law of heredity in mind, to obtain definite results, whether they be positive or negative.”