The PDX model, the full name of the human-derived tumor xenograft model, is a transplanted tumor model formed by implanting patient-derived tumor tissue and primary cells into immunodeficient mice.
Compared with the traditional cell-derived xenograft (CDX), the PDX model has not been cultured in vitro, and it has better maintained genetic characteristics and heterogeneity of the primary tumor. The experimental results have better clinical predictability and can be the best animal model of tumor at this stage.
In order to understand the origin of tumors, early scientists used the “Cancer Genesis” method to induce the formation of spontaneous tumors. They used various methods to induce normal cells to become cancerous in order to form tumors in healthy tissues, but they all ended in failure.
Next, scientists tried to reproduce human tumors by directly transplanting human tumors into animals.
The first experiment that dates back to transplanting human tumors into animals was conducted by French surgeon Peyrilhe in 1775. He injected crude extracts of human breast cancer into a dog. At the beginning, scientists conducted this experiment mainly out of curiosity. In order to determine the heredity of tumors, they were interested in transplanting tumors into animals to observe the pathology of this unknown disease. Although this experiment ended in failure, with Peyrilhe’s attempts, a century has passed by pioneers of oncology in the field of human tumor xenograft models.
In 1807, Dupuytren tried various methods to transplant human tumors into animals, including inoculating tumor tissue into the animal’s abdomen, injecting tumor tissue mixture into the animal’s abdominal cavity or vein, and inoculating pus from ulcerative cancer patients.
In 1840, Langenbeck designed another similar experiment, injecting human humeral myeloid carcinoma tissue fluid into a dog’s vein. Two months after the vaccination, he found several round nodules in the dog’s lungs.
In 1851, Lebert and Follin injected breast cancer tissue into the jugular vein of a dog. Although the animal died 15 days later, an autopsy revealed that there were nodules around the heart.
Unfortunately, in the above two cases, scientists cannot confirm whether the observed nodules are the direct result of tumor transplantation or the spontaneous formation of tumors. In Langenbeck’s case, the pathologist Virchow believes that the nodules produced here are closer to spontaneous cancer in dogs than to humans.
Although in this century, the development of human tumor xenogeneic models has not formed a constructive breakthrough, history has proved that the continuous attempts of these scientists have laid a solid foundation for the emergence of the PDX model.
In 1938, Greene reported the results of his successful transplantation of human uterine adenomas into rabbits. Between May 1934 and December 1937, Greene transplanted human uterine adenomas into the subcutaneous tissues, muscles, peritoneal cavity, testes and anterior chamber of 83 rabbits by injecting cell suspension or transplanting tumor tissue masses. 61 tumor-bearing animals died at different stages of tumor development, 8 died of tumor metastasis, and 14 were under normal observation. Calculated from the date of tumor discovery, tumor survival time is 5 to 20 months, with an average of 12 months; if calculated from the date of reproductive disorders, tumor survival time is 14 to 29 months, with an average of 19 months. In all cases where the tumor duration is more than 1 year, the tumor has metastasized, and the tumor in the eye has successfully grown for 6 generations through continuous metastasis.
Different tumor transplant methods
While continuously exploring feasible methods for transplanting human tumors, scientists have also performed many experiments to test the transplantation efficiency of different hosts by implanting tumors into the cheek pouches of rats, hamsters, dogs and chicken embryos.
In 1951, Toolan designed a plan to successfully transplant tumors by pre-treating rats and mice before transplantation. In the protocol of treating rats and mice with X-ray irradiation, the rats receive 3 times of 200r whole body X-ray irradiation every other day, and the mice receive 4 times of 150r whole body X-ray irradiation every other day. Then Toolan will include Cell suspensions of 100 human tumors, including epidermoid tumors, melanomas, breast tumors, leiomyomas, etc., were implanted in the subcutaneous tissues of rats and mice that had been irradiated with X-rays, 33 of which were in the first place. At the end of generation (8 days), there were no mitotic cells. 34 cases showed cell proliferation at the end of the first generation, but failed to transfer to the second generation. 33 cases were transplanted for two or more generations and had active signs of growth and blood vessel formation. Among them, the spread of epidermoid tumors is the most significant.
Toolan effectively proved the important role of host immunity in transplantation success. Although the use of pretreated animal hosts for human tumor transplantation has been successful, these methods still have some shortcomings that make it not widely used for a long time. To a large extent, this is due to the expected changes in the application of human tumor models. With the advancement of society’s knowledge and understanding of cancer, scientists have begun to consider the possibility of using human tumor models as drug screening platforms, while pretreatment of animal hosts has not provided ideal experimental conditions.
To be continued in Part II…