How tumors control their surroundings in order to advance is a long-standing mystery that scientists from all around the world have been attempting to solve for years.

For decades, researchers focused on tumors’ inherent behavior, but not on their environment.

A study released this week in the prestigious journal Nature Cancer details how this critical process for melanoma progression takes place: exosomes travel and home to the sentinel lymph node -the lymph node where metastasis first occurs- from which they remotely prepare a favorable environment for metastasis -the pre-metastatic niche-.

In this work, the researchers discovered that the NGFR molecule is at the heart of the entire process, and that inhibiting it significantly reduces metastasis in animal models. The reduction in metastasis was obtained with the use of THX-B; this molecule is currently being evaluated for the treatment of various illnesses, which will expedite its potential application in the treatment of tumors.

They also propose NGFR as an early melanoma metastasis biomarker that can be used to establish risk groups and predict metastasis in melanoma patients.

“A higher number of NGFR-expressing metastatic cells in the sentinel lymph node correlates with a worse disease prognosis,” said Susana Garcia Silva, co-first author of the study.

Melanoma, in contrast to other types of skin cancer, is one of the most aggressive tumors, and it can metastasize even while the primary lesion is still quite small. Due to the lack of early illness signs or disease prediction markers, it is critical to develop innovative treatments while simultaneously ensuring that patients receive timely and correct diagnosis in order to improve their prognosis.

Metastasis is the leading cause of cancer death, accounting for 90% of all cancer fatalities. The majority of the time, they are discovered too late.

“If we can identify when a tumour is going to metastasise, even before it happens, during soil preparation, it will be easier to treat it and to contain it,” said Héctor Peinado, a researcher at the Spanish National Cancer Research Centre (CNIO).

Although exosomes, which are nanovesicles secreted by all cell types, including tumor cells, have been known for more than 30 years, they have only recently been examined. Peinado revealed how tumour cells release exosomes, which send biological information to the surrounding microenvironment to train it and encourage metastasis even before the tumour cells themselves travel through the body, in David Lyden’s lab in the United States in 2012.

“Until a few years ago, the microenvironment surrounding the tumours was overlooked. Now we know that the communication of tumours with their local environment and the rest of the organism is fundamental to understand cancer and its complications,” said Peinado in 2015, shortly after joining the CNIO to start his Microenvironment & Metastasis Group.

Melanoma cells, like many other tumor cells, move and spread throughout the body primarily through the bloodstream and lymphatic system. These circulating tumor cells settle in lymph nodes, which operate as a reservoir or warehouse, and from there they carry out the modifications that lead to the establishment of a pre-metastatic niche that promotes colonization of other organs.

“In this study, we focused on the mechanisms of what could be called the earliest stages of metastasis,” explained Peinado.

Exosomes generated by melanoma cells are recruited by lymphatic endothelium cells in the lymph nodes, according to a study published in Nature Cancer after seven years of comprehensive research. In these cells, the exosomes, through the NGFR molecule, encourage further branching of the lymphatic vasculature as well as adherence of cancer cells, which will allow them to survive and move to other organs and places.

“Melanoma cells secrete exosomes carrying NGFR to manipulate the behaviour of lymphatic endothelial cells and facilitate metastasis.”

“We knew that melanoma cells that initiate metastasis increase NGFR production, but nothing was known about a possible role of NGFR in exosomes and its effects outside the tumour.”

After learning about this molecule’s significance in the early stages of melanoma metastasis, the researchers chose to investigate the effects of blocking it during tumor cell proliferation in mice. They employed a genetic strategy to delete NGFR from exosomes and a pharmacological approach to use the NFGR inhibitor THX-B to accomplish this. Metastasis was dramatically decreased in both cases, paving the path for a potential new treatment to battle metastasis.

This could be one of the first treatments to combat metastasis in its earlier phases, when it has the best chance of succeeding.

The THX-B inhibitor is being researched for other disorders such diabetic retinopathy, but its usefulness in the therapy of cancer has yet to be determined.

These findings could be applied to preventing metastasis in other cancers that overexpress NGFR.

The number of metastatic cells expressing NGFR in lymph nodes also predicts disease progression in melanoma patients, according to the study.

“Analysis of these cells in the lymph nodes could serve as an important biomarker of disease progression and for early diagnosis,” concluded the study author.

Source: 10.1038/s43018-021-00272-y

Image Credit: iStock

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