How Tumors Stay Alive and Make Their Way Through the Body Revealed. An international group of researchers – coordinated by Professor Stefano Santaguida, Group Leader at the Department of Experimental Oncology of the European Institute of Oncology and professor of Molecular Biology at the State University of Milan – has identified a protein, called p62, that plays a crucial role in the molecular mechanism capable of supporting the vital processes of the tumor cell, including metastases. The results of the studysupported by the Airc Foundation for Cancer Research and the Cariplo Foundation, were published today in ‘Science’The ‘bible’ of scientific journals has dedicated its cover to research.
Chromosomal instability and cellular chaos
It all starts with chromosomal instability, one of the traits that characterize most tumor cells and which consists in the high frequency of errors in the segregation of chromosomes into ‘daughters’ during cell division. This instability creates a situation of cellular chaos that contributes to the anarchic programs of tumor cells, including replicating endlessly and surviving external attacks, the researchers explain. Furthermore, chromosomal instability causes tumor cells to have different chromosome arrangements (karyotypes), and this is an advantage for cancer, since at least some of the tumor cells will have a karyotype capable of resisting drugs. Another consequence of chromosomal instability is the formation of micronuclei, abnormal structures that are located outside the primary nucleus of the cell and that are able to induce ‘disregulated’ chromosomes to catalyze cellular chaos.
The envelope of these microstructures is very fragile and often defective, so the DNA they contain is not sufficiently protected. Indeed, it is often exposed to the cytoplasm and suffers persistent damage, which creates an environment favorable to tumor development. “We have known for some time that micronuclei are tumorigenic, but we did not know why. With our study we understood that the original problem is the inability to repair the nuclear envelope and we committed ourselves to finding the cause. We thus discovered that this inability is linked to p62, a multitasking protein with multiple cellular functions”, underlines Santaguida.
“However, p62 had never been linked to chromosomal instability before. Through complex cellular mechanisms that we have identified and characterized in detail at the molecular level – he explains – We have demonstrated that p62 inhibits the action of the ‘repairers’ of the nuclear envelope of the micronucleus. The latter, left without defenses, collapses, leaving the chromosomes contained at the mercy of chaos. Thus chromosomal instability increases and tumor cells receive more than one advantage, becoming stronger, growing, defending themselves from drugs and migrating within the organism”.
“Our discovery has a clear impact on clinical practice because, from our analyses, it appears that tumors characterized by chromosomal instability and with high levels of p62 have a worse prognosis. The p62 protein could therefore from today be considered a prognostic marker and an important therapeutic target“, concludes the researcher.
The study was conducted in collaboration with international centers of excellence in oncology, including, in the United States, the Memorial Sloan Kettering Cancer Center in New York City, Harvard Medical School in Boston, the University of Texas Southwestern in Dallas, the Fred Hutchinson Cancer Research Center in Seattle; in Israel, the University of Tel Aviv; and in Italy, the University of Palermo, the San Raffaele Hospital in Milan and the Ifom in Milan.
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