Scientists have found a mechanism that might help them stop breast cancer from spreading to the bones – a breakthrough that could improve survival rates of thousands of patients each year. And even more excitingly, they’ve also found an existing drug that can stop the metastasis from happening in mice.
The team found that before a tumour spreads, it releases an enzyme that starts breaking down bone tissue and forming holes, essentially preparing them for the arrival of the cancer cells. They now hope that by blocking this enzyme, known as LysYl Oxidase or LOX, they might be able to stop the disease progression in certain patients.
Publishing in Nature, the researchers explain that the results could help the almost 12,000 people in the UK, 40,000 in the US, and 3,000 in Australia who die from breast cancer each year. The majority of these deaths occur after the disease has spread to other parts of the body, a process known as metastasis – and in roughly 85 percent of these cases, the bone is the first site that breast cancer attacks.
“We are really excited about our results that show breast cancer tumours send out signals to destroy the bone before cancer cells get there in order to prepare the bone for the cancer cells’ arrival,” one of the lead researchers, Alison Gartland, from the University of Sheffield in the UK, said in a press release.
“This is important progress in the fight against breast cancer metastasis and these findings could lead to new treatments to stop secondary breast tumours growing in the bone, increasing the chances of survival for thousands of patients.”
The researchers also showed that, in mice, a class of drugs called bisphosphonates, which are used to treat bone mass loss in osteoporosis patients, was able to prevent the holes forming in the bones and stop the spread of breast cancer.
The discovery only applies to the roughly one-third of patients that have oestrogen receptor negative (ER negative) breast cancer, which is particularly hard for doctors to treat. But the research will help scientists understand more about how other cancers prepare to spread around the body.
“The next step is to find out exactly how the tumour secreted LOX interacts with bone cells to be able to develop new drugs to stop the formation of the bone lesions and cancer metastasis,” said Gartland. The research could also lead to new treatments for debilitating bone conditions.
“The reality of living with secondary breast cancer in the bone is a stark one, which leaves many women with bone pain and fractures that need extensive surgery just when they need to be making the most of the time they have left with friends and family,” said Katherine Woods from the Breast Cancer Campaign that partly funded the research.
Breaking cancer cells’ ‘legs’
The long, thin protrusions that help cancer cells to move are called filopodia. They are an extension of a set of “broad, sheet-like” fibers called lamellipodia, which can be found around the edges of the cell.
The suffix “-podia” (or “-podium,” singular) comes from the Greek language and means “something footlike.”
Essentially, lamellipodia and filopodia are tiny “legs” that help healthy cells to move within the tissue. But in cancerous cells, lamellipodia and filopodia are produced in excess.
The researchers used so-called nanorods, made of gold nanoparticles, to obstruct these tiny legs.
With the help of nanotechnology, scientists are able to reduce the size of certain materials to a nanoscale – with “nano” meaning the billionth part of a meter – at which point these materials start to show new chemical and physical properties.
Prof. El-Sayed and colleagues introduced the nanorods locally. The nanorods were covered with a coating of molecules, called RGD peptides, that made them attach to a specific kind of protein called integrin.
“The targeted nanorods tied up the integrin and blocked its functions, so it could not keep guiding the cytoskeleton to overproduce lamellipodia and filopodia,” explains co-author Yan Tang, a postdoctoral assistant in computational biology.
A cytoskeleton is the support structure of a cell, responsible for giving it a shape. It also has additional functions, with one of them being to form the filopodia protrusions.
Method could kill cancer cells
The experiments revealed that simply binding the nanorods to the integrin delayed the migration of the cancer cells.
Importantly, this method avoided healthy cells, which could make this therapy drastically less damaging for patients who undergo toxic chemotherapy treatment.
“There are certain, specific integrins that are overproduced in cancerous cells,” explains Moustafa Ali, one of the study’s first authors. “And you don’t find them so much in healthy cells.”
In the second stage of the experiment, Prof. El-Sayed and team heated the gold nanoparticles with a laser of near-infrared light. This effectively stopped the migration of the malignant cells.
“The light was not absorbed by the cells, but the gold nanorods absorbed it, and as a result, they heated up and partially melted cancer cells they are connected with, mangling lamellipodia and filopodia.”
In this experiment, not all cancer cells were killed, as this would have prevented the researchers from examining whether or not they successfully stopped them from migrating. However, the researchers say that the method could be adjusted to kill the malignant cells.
Prof. El-Sayed and his colleagues have previously conducted similar experiments in mice, in which they applied the same method. The former research found no toxicity from the gold for up to 15 months after the treatment.
The researchers hope to soon be able to treat “head, neck, breast, and skin cancers with direct, local nanorod injections combined with the low-power near-infrared laser.”
The laser could reach the gold nanorods at 4 to 5 centimeters deep inside the tissue, and deeper tumors could be treated with deeper nanorods injections, the authors say.
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