Researchers at IMIM-Hospital del Mar, with the participation of Incliva and other research centers, have discovered the mechanism by which tumor cells become resistant to chemotherapy in colon and rectal cancer. Research shows that oxaliplatin, which is given in some cases of colon cancer accumulates in healthy cellss causing resistance to treatment and contributing to the regeneration of the tumor.
The study, published in Nature Communicationshighlights the role of the non-tumor cells and opens the door to a precision oncology strategy based on the diversity of sensitivity mechanisms and a more personalized action, as reported by Incliva in a statement.
According to this research, one of the types of chemotherapy used to treat advanced colon and rectal cancer the platinum-based one accumulates in healthy cells surrounding cancer cells and, as a consequence, can decrease the sensitivity of the cancer to treatment.
This is demonstrated by a study by the Instituto Hospital del Mar de Investigaciones Médicas (IMIM-Hospital del Mar), with the participation of the Instituto de Investigación Sanitaria Incliva, the Catalan Institute of Oncology (ICO), the Vall d’Hebron Institute of Oncology ( VHIO), the Institute of Biomedical Research (IRB) of Barcelona, the University of Oviedo and the CIBER del câncer (CIBERONC).
A large number of cancer patients receive platinum-based treatments. But a good number of tumors have the ability to generate resistance in this approach. To find out the reasons, this work has analyzed samples from patients with advanced colon and rectal cancer and validated the results in mouse models.
Thus they have been able to see how, in these treatments, platinum accumulates in a “very prominent” way in healthy cells surrounding the tumor, especially in fibroblasts, the cells that help make tissue. In addition, this accumulation is maintained for long periods of time, more than two years after the end of treatment. To do so, techniques developed in the field of geology applied to biological samples have been used.
The effect of platinum on fibroblasts
The researchers were able to see how this accumulation of platinum in the fibroblasts generated the activation of certain geneslinked to a poor response to chemotherapy treatment and tumor progression, including those related to the TGF-b protein, which stimulates the fibroblasts themselves and causes them to help tumor cells that have survived chemotherapy to progress again. new.
This leads Dr. Alexandre Calon, head of the Tumor Microenvironment Translational Research Laboratory at IMIM-Hospital del Mar, and who leads the study, to point out that “the activation of fibroblasts by oxaliplatin can generate mechanisms of resistance to the same chemotherapy”.
Currently, there are no predictive markers of response to chemotherapy in colon and rectal cancer. In this sense, this work has made it possible to verify with samples from thirty patients, from before and after undergoing chemotherapy, that the levels of another protein, periostin, are an indicator of TGF-b activity in fibroblasts and work as a good marker response to chemotherapy.
Thus, this response was poor in those people whose periostin levels were high before receiving the first doses or in those who were low, but shot up after treatment. Likewise, in mouse models it was certified that in those in which higher levels of this protein were provoked, the treatment against the tumor loses effectiveness.
“We have discovered a mechanism of resistance to oxaliplatin and a marker of this resistance in patients with colon and rectal cancer,” says Dr. Jenniffer Linares, first author of the study. A fact that shows, according to Calon, that the environment of the tumor must be taken into account when developing cancer treatments. “Chemotherapies are evaluated in relation to their effectiveness on cancer cells, not on the healthy cells that make up the tumor microenvironment, which protects the tumor,” he pointed out.
Find a way to get over it
Researchers are now working to develop a new kind of approach that allows restoring the capacity of chemotherapy on tumor cells. They have done so in a new study pending publication that is based on the combination of the medication with a peptide that prevents platinum from accumulating in fibroblasts.
In this sense, Dr. Andrés Cervantes, scientific director of the Incliva Health Research Institute and researcher at the CIBER on Cancer (CIBERONC), has detailed that “the study reinforces the role played by non-tumor cells may have on the response to chemotherapy” and that “these discoveries open the door to a precision oncology strategy that makes it possible to recognize the diversity of sensitivity and resistance mechanisms to treatments, acting differently depending on them and facilitating a more personalized action”.
As Clara Montagut, head of the gastrointestinal tumor section at Hospital del Mar and a CIBERONC researcher, says, “this study is an important step towards understanding why chemotherapy treatment does not work the same in all cancer patients, and be able to prevent or reverse resistance to chemotherapy. It is also a relevant step to understand that cancer treatment has to take into account not only cancer cells, but also the healthy cells that surround the tumor, the so-called microenvironment.”
As he stressed, 2the next critical step will be to develop pharmacological strategies that act on the cancer cell and modulate the microenvironment in favor of the removal of the tumor”. The work has had the support of the Carlos III Health Institute and the Spanish Association Against Cancer (TuMICC project, Junior Clinician fellowship).