"Family tree" of prostate cancer: details

Scientists have traced the evolution of cells of lethal metastatic prostate cancer

Vyacheslav Kalinin, "Elements"

In a cancerous tumor, evolution is constantly taking place, leading to the emergence of various cell clones in the primary tumor. As a result, clones are formed that can form metastases in other organs and tissues. A new article by a large international group of researchers describes the complex process of metastasis in prostate cancer. New data have been obtained on the molecular mechanisms of the development of resistance to therapy, which may be useful for the development of new drugs that block the pathways of resistance development.

Metastases are the cause of death in 90% of cancer cases. Despite the obvious clinical significance of metastasis processes, little is known about the principles underlying them. It is known that in the process of development, tumors undergo evolution. During division, tumor cells accumulate various mutations and give rise to various clones that form a heterogeneous (heterogeneous) primary tumor. Cells of one or several unique clones acquire the ability to penetrate into blood or lymphatic vessels and disseminate — spread to other organs or tissues (Fig. 1). There they form secondary tumors — metastases.

Fig. 1. The scheme of the occurrence of metastases. Primary tumor cells capable of metastasis, with the help of the collagenase type IV enzyme, penetrate into a blood or lymphatic vessel and spread throughout the body. Metastasis — a secondary tumor — can form far from the primary one. Drawing from the website en.wikipedia.org .

The currently accepted and experimentally confirmed theory considers the unique single cells of the primary tumor capable of dissemination to be the originators of metastases. But more recently, data were obtained on model mice indicating the possibility of metastases from several clones of cells of a heterogeneous primary tumor and the interaction between individual clones during the formation of metastases.

To determine whether there are polyclonal metastases (which give rise to various clones of primary tumor cells), the authors examined the clinical material of patients with metastatic prostate cancer. Using the new generation sequencing technology, they performed a complete analysis of the genomes of 51 primary tumors and metastases of 10 patients. The average "depth" of sequencing (the number of repeated reads per nucleotide) was 55 (for comparison: one reading is enough for the primary analysis of the human genome). In some cases, for a more detailed analysis, the "depth" was increased to an average of 471. In all samples in the genomes, many nucleotide substitutions, deletions and insertions, rearrangements of the chromosome structure and changes in the number of copies of various parts of the genome were observed. From 181 to 429 anomalies were found in patients. With the help of bioinformatic methods, the sequences of the occurrence of various mutations were established. By tracking mutations, the relationships of metastases with the primary tumor and with each other were determined. "Phylogenetic trees" have been constructed showing the gradual evolution of metastases (Fig. 2).

Fig. 2. Subclonal structure of tumors and metastases in ten patients with prostate cancer. The mutations present in the "trunk" (primary tumor, gray lines) and additional mutations found in metastases are shown. The length of the branches corresponds to the number of additional anomalies acquired. The organs and tissues in which metastases have been localized are signed at the bottom. Abbreviations: AR — androgen receptor; amp — amplification; HD — homozygous deletion; Abd. para — abdominal paraaortic region; diaph. — diaphragm; ing. — groin area; subclav. — subclavian area; super. — superficial. Figure from the article under discussion by G. Gundem et al. in Nature

Most of the mutations found are already known as drivers of oncogenesis in prostate cancer. Metastases-"branches" — subclones of the parent clone of the primary tumor — inherit mutations from the primary tumor and accumulate new mutations. There were quite a lot of "branches", which indicates the accumulation of various new mutations in metastases and the formation of various metastases-subclones. Additional driver mutations occur in metastases, including mutations associated with the acquisition of resistance to traditional prostate cancer therapy — androgen receptor suppression. There was also evidence of the formation of some metastases by two or more clones of cancer cells. These clones can functionally interact with each other to ensure more efficient development of metastases. It also turned out to be a new established fact that some metastases are formed not by primary tumor cells, but by the dissemination of cells of previously formed metastases (Fig. 3).

Fig. 3. The scheme of the spread of metastases in prostate cancer. The distribution of various subclonal populations of metastatic cells is indicated by arrows of various colors. Metastases can form not only subclones of primary tumor cells (red arrows), but also already formed metastases. Two-sided dotted arrows indicate that it is not known for sure which way the spread of metastases went. The blue and blue arrows indicate polyclonal metastasis. Prostate — prostate, Blade — bladder, Right pelvic lymph node — right pelvic lymph node, Seminal vesicle — seminal vesicle, Left humerus bone marrow — bone marrow of the left humerus. The scheme from the synopsis to the discussed article in Nature

The obtained results reveal the molecular mechanisms of the emergence of resistance to therapy in prostate cancer. Prostate cancer tumors are known to depend on androgen hormones. Therefore, blocking the function of these hormones, for example, by blocking the androgen receptor works as an effective therapy and leads to tumor degradation. But the tumor can relapse if it becomes resistant to therapy. Most often this happens due to the activation of the androgen receptor function. Anomalies activating this function were found in metastases: amplifications of the receptor gene and mutations in the gene activating the receptor itself. Anomalies of other genes associated with the signaling mechanism of the receptor (for example, the FOXA1 gene), with workarounds for the development of resistance (amplification of the MYC gene, mutation in the CTNNB1 gene) were also found. One or several anomalies of this kind were found in all patients. As a rule, they were observed in metastases formed during treatment. But in two cases these were early events: in one there was an amplification of the receptor gene, in the other there was an activating mutation.

Thus, the authors were able to trace the evolution of genomes in prostate cancer extremely clearly from the initiation of oncogenesis through the acquisition of metastatic potential to the development of resistance to drug therapy. Anomalies that block the functions of tumor suppressor genes usually occur as isolated events. At the same time, mutations associated with the development of resistance to therapy appear in various metastases as convergent evolution — various mutational events with the selection of emerging clones based on resistance to therapy. In this sense, the evolution of metastatic prostate cancer is similar to the evolution of populations of living organisms. The results obtained reveal in detail the complex process of metastasis, allow a deeper understanding of the mechanisms of resistance to drug therapy in prostate cancer and may be useful for the development of new drugs that block the pathways of resistance development.

Sources:
1) G. Gundem et al. The evolutionary history of lethal metastatic prostate cancer // Nature. 2015. V. 520. P. 353–357.
2) M. M. Shen. Cancer: The complex seeds of metastasis // Nature. 2015. V. 520. P. 298-299. (Popular synopsis to the article G. Gundem et al.)

Portal "Eternal youth" http://vechnayamolodost.ru02.06.2015