“It’s not just looking inside the tumor, but also looking outside,” says the scientist at National Cancer Research Center (CNIO), Hector Peinado. How tumors manipulate their exterior to advance is one of the great questions that have been sought to answer for years. For decades, “researchers have focused on studying the intrinsic behavior of the tumor to fight it, but not everything that surrounds them.”
Peinado leads the CNIO in the Microenvironment and Metastasis Group, which studies the mechanisms involved in metastatic progression, including how nanoparticles released by tumors called exosomes they manipulate the tumor microenvironment to promote metastases.
The NGFR molecule directs the entire process of melanoma progression and its blockade drastically reduces metastases in animal models
In a job ad this week Nature Cancer, The group describes how this critical process for advancing the melanoma: exosomes travel and remain in the sentinel node —Lymph node where metastasis initially occurs— where they remotely prepare the enabling environment – the premetastatic niche – to promote metastasis.
In this work, they observed that the NGFR Molecule directs this entire process, and blocking it drastically reduces metastases in animal models. This reduction is achieved by THX-B Molecule, which is already being tested for the treatment of other pathologies, which will accelerate its possible use for the treatment of tumors.
Scientists also propose NGFR as a new biomarker of early metastasis of melanoma to define risk groups and anticipate it. “A greater number of metastatic cells expressing NGFR in the sentinel node correlates with a worse disease prognosis,” he says. Susana Garcia Silva, co-first author.
Melanoma is one of the most aggressive tumors, as it can lead to lymph node metastases from the very beginning.
Unlike other skin cancers, melanoma It is one of the most aggressive tumors and can lead to lymph node metastases from the very beginning, when the lesion is very small.
There are no early disease markers or disease prediction, hence the importance not only of new treatments, but of a early diagnosis and accurate to improve the prognosis of patients.
Metastasis accounts for 90% of deaths for cancer. In most cases it is diagnosed too late. “If we manage to detect that a tumor is going to metastasize, even before it happens, it will be easier to treat it and we will be able to stop it”, says Peinado. Although exosomes (nanovesicles expelled by all types of cells, including tumor cells) were discovered more than 30 years ago, they were not extensively studied until a few years ago.
In 2012 Peinado discovered in the laboratory of David Lyden, in the US, as tumor cells release exosomes, which transfer biological information to the microenvironment that surrounds them to educate you and promote metastases even before the tumor cells travel through the body. “Until a few years ago, the microenvironment that surrounds tumors went unnoticed. Now we know that the communication of tumors with the local environment and with the rest of the body is essential to understand cancer and its complications”, he declared in 2015.
We now know that the communication of tumors with their local environment and with the rest of the body is essential to understanding cancer and its complications.
Héctor Peinado (CNIO)
Melanoma cells, like many cells from other tumors, travel and spread throughout the body primarily through the blood circulation it’s from lymphatic system. These circulating tumor cells are housed in lymph nodes that act as a reservoir or storage, from where they carry out the modifications for the formation of the premetastatic niche which will favor the colonization of other organs. “In this work, we wanted to focus on the mechanisms of what we could call the first moments of metastasis”, explains Peinado.
After seven years of exhaustive analysis, the researchers described that the exosomes released by melanoma cells are recruited by the lymph cells endothelial lymph nodes. In these cells, exosomes promote – through NGFR Molecule – a greater branching of the lymphatic vasculature and the adhesion of tumor cells that will allow their survival and migration to other locations. “Melanoma cell exosomes secrete NGFR to disrupt lymph endothelial cell behavior and facilitate metastasis.”
Mouse lymph node in which lymphatic capillaries (green) and tumor exosomes (red) are visualized that will direct the first moments of metastasis. / CNIO
Possible first treatment against this metastasis
“We knew that melanoma cells that initiate metastases increase NGFR production, but nothing was known about a possible role of NGFR in exosomes and its influence outside the tumor,” explains Peinado. Having discovered the role of this molecule in the early development of melanoma metastasis, the team decided to study the consequences of its block in the expansion of tumor cells.
To do this, they used a genetic approach, in which NGFR removed of exosomes, and a pharmacological approach in which they used the inhibitor of NFGR, called THX-B. In both cases, metastases were drastically reduced, which paves the way for a possible new treatment to fight them. This therapy would become one of the first to deal with metastasis in its early stages, when it is most likely to deal with it.
Genetic or pharmacological blocking of the NGFR molecule drastically reduces melanoma metastasis
The THX-B inhibitor is being studied in the treatment of other diseases, such as Diabetic retinopathy, but its effectiveness in treating cancer had not been explored. Now experts are developing its use for clinical application. These results can be extended to blocking metastases in other types of tumors that overexpress NGFR.
Finally, the work shows in melanoma patients that the number of metastatic cells expressing NGFR in lymph nodes predicts disease progression. “The analysis of these cells in lymph nodes can serve as an important biomarker of their progression and early diagnosis”, concludes the researcher.
García-Silva et al. Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through a p75NTR / NGFR-dependent mechanism. Nature Cancer, 2021. DOI: 10.1038 / s43018-021-00272-y
Rights: Creative Commons.