VHIO study exploits premature aging of cells as a treatment strategy for HER2+ breast tumors

Research led by the Vall d'Hebron Institute of Oncology´s Growth Factors Group headed by Joaquín Arribas, shows the inhibition of certain pro-tumoral factors secreted by cells showing signs of premature aging to be a novel strategy for anti-cancer therapy. The study, published this month in the Journal of the National Cancer Institute (JNCI), was supported by the Spanish Association against Cancer (AECC), the Carlos III Institute of Health, and the Breast Cancer Research Foundation (BCRF). The current issue of this prestigious publication also ran a special editorial to discuss the use of monoclonal antibodies against Interleukin-6 (one of the pro-tumoral factors studied by Joaquin´s group) in combination with anti-HER2 therapy, as a new therapeutic approach.

This latest study, which focused on HER2+ breast cancer, explored natural senescence as opposed to artificially induced senescence described in previous work. Senescence is a phenomenon by which cells stop dividing and initiate a process which has certain similarities with aging, eventually leading to cell death. This mechanism which may be considered to be beneficial for patients is not always so in practice. While senescent tumor cells no longer proliferate, they continue secreting a series of factors important for tumor growth and distant metastasis. Senescence of tumor cells is therefore a double edge sword – while it does not promote tumor growth, it potentiates the aggressiveness of the disease.

Findings have confirmed that the percentage of senescent cells in a tumor is relatively low at a constant 2-5%, “but if we consider the cells side by side in three dimension, we can see that senescent cells have a tremendous capacity to interact with a large number of tumor cells: one senescent cell producing these pro-tumoral factors is located barely three cells away from the furthest cell. This means that the cascading effect caused by such secretion impacts majorly on neighboring cells,” explains first author Joaquín Arribas, ICREA Professor, Director of Preclinical Research at VHIO and Principal Investigator of VHIO´s Growth Factor Group.

The importance of the cancer secretome

This cellular senescence has also been studied in vitro (in tumor cells), in vivo, and in experimental models know as PDX or avatar mice. Real patient tumor samples are implanted in these mice as well as in genetically modified laboratory animals. Results have been confirmed in all three scenarios. The experimental model that most faithfully reproduces the tumor, as its mirror image, is the PDX model, but to be able to develop the tumor the receiving animal's immune system must be suppressed, otherwise it would reject cellular implantation thus ruling out the development and study of the tumor. For this reason the tumor was studied in two different in vivo models with similar results in both cases.

“The challenge is to totally inhibit the secretion of pro-tumoral factors by senescent cells,” explains Joaquín. “In the experimental models we have already managed to block one of these, Interleukin 6 (IL-6).” The next goal will be to completely inhibit these senescent cells with therapies that block them from secreting pro-tumoral factors. “What really interests us is inhibiting the production of pro-tumoral factors so that senescence becomes a truly undisputed anti-tumor mechanism,” Arribas continues.

Tumor cell senescence: not so harmless

A study previously conducted by this same group, published in Cancer Research in 2013, also under the leadership of Joaquín Arribas, already established that cells undergoing premature aging within a tumor are not harmless and that, contrary to what was previously upheld, senescent cells render others more malignant with a greater capacity for metastasis.

“We must therapeutically act against these cells, focusing especially on the factors they secrete -- simply waiting for cell death makes the neighboring cells more aggressive,” comments Arribas. The secretion of these harmful cell factors must therefore be eliminated. Although the current study focused on HER2+ tumors, findings may be extrapolated to other tumor types, representing an important line of research to come.