Cancer is a skilled lobbyist, but an unfamiliar environment will confuse it

A cancer cell imprisoned in a laboratory needs the right kind of habitat to show its true colours, says Professor Tuula Salo.

Professor of Oral Pathology Tuula Salo investigates oral cancer and especially the interaction between cancer cells and their surrounding tissue.

“Earlier, cancer researchers focused mostly on the cancer cells themselves, but now we understand that the interaction between the cancer cells and their environment is key to how cancer grows and spreads,” she notes.

Among other things, Salo’s research group has noticed that oral tongue squamous cell carcinoma can invade healthy tissue either through ‘budding,’ that is, as small clusters of cells, or as a disc-like formation. Invasion through budding is more efficient, resulting in a poorer prognosis for the patient.

“Nowadays we can see directly from the sample which method of invasion the tumour is using, and based on this we know how aggressively it will spread.”

The spread of cancer is also affected by the quantity and quality of the tissue surrounding it. In dense tissue, cancer will spread faster than in soft tissue, and If the tissue surrounding the cancer cells is immune-rich, less invasion of cancer cells was noted.

“Collagen fibrils make it easier for cancer to spread, they effectively lay a well-founded road for the cancer cells to travel. Cancer cells are also able to produce enzymes that break down intercellular material and clear a path for them to attack healthy tissue,” Salo explains.

The original malignant tumour, primary cancer, is accustomed to the environment where it was born. However, the cancer cells that migrate to form metastases have to adjust to a new living environment. The primary cancer acts like an effective helicopter parent: it sends messages to lymph nodes in advance to mould them into a favourable environment for its offspring.

A strange environment confuses cancer cells

Cancer cells taken from human malignant tumours are usually examined in culture media of animal origin, which makes the environment significantly different from the original. Few years ago Salo started wondering how much and in what way the inauthentic environment could affect the behaviour of cancer cells and how these differences could impact research findings.

“The central thing about cancer is its ability to spread in and invade healthy tissue. In order to make this ability visible already at the cell culture stage, the cells must have the correct living environment.”

An extracellular matrix derived from mouse EHS sarcoma is commonly used as a culture medium. However, human and mouse tissue have significant differences, for example, in their protein composition. In addition, animal models traditionally involve transplanting cancer cells under the skin of the mouse.

“But if you plant cancer cells taken from the mouth of a human to the bum of a mouse, of course they won’t behave in the same way as they do in their original environment!”

For a long time, Salo tried to figure out how to create an accurate environment for human cancer cells.

“I was in the shower when it finally hit me: why not use myomas!”

Myomas are common, benign muscular tumours of the womb. Symptomless myomas require no treatment, but if they grow too large or cause adverse symptoms, they are surgically removed. Salo acquired these myomas for her research group with ethical permission for use in research purposes.

She also got a meat slicer.

“We carved the tumour into thin slices – a bit like ham slices – by the way, I’ve stopped eating ham!”

“Then we took this human tissue to make a gel that is suitable as a culture medium using the same method that is used to make the commonly used animal-based extracellular matrix. We named our product Myogel.”

A happy cancer cell – more reliable results?

When the researchers compared Myogel with the commonly used Matrigel culture medium, they noticed that 66 per cent of the proteins in the products were different.

“For example, an epithelial tumour, carcinoma, thrives and grows excellently in human-derived Myogel where the cancer cells receive a little additional boost from the Tenascin C protein in the gel. As a result, the cancer cells progressed very rapidly in the tissue, Salo says.

“It is important to understand that cancer cells react differently to different culture media. When the effectiveness of an anticancer drug is examined in a cell culture, the cancer must first be properly activated to see whether the drug can stop it or not.

All parts of the tissue have an impact on how effectively the cancer will invade it,” Salo stresses.

“When we rinsed the myoma tissue, the progress of the cancer slowed down. That means that the soluble components of the tissue, such as proteases and cytokines, are also essential for cancer cells.”

95 per cent of the anticancer drugs currently in development will fail in phase III of clinical trials, which are the first extensive tests on patients. Failure at this stage usually means that the drug does not prove to be effective enough.

“We have been investigating whether we could get information on the actual efficacy of the drugs on humans already at earlier stages of development, if an appropriate culture medium is used. The research findings on this have not been published yet, but right now they look promising,” Salo says.

Lymph nodes as a culture medium for metastatic cancer cells?

Salo’s research group has also examined how the carcinoma cells of a primary tumour and metastases grow in a culture medium made of lymph nodes from pigs, Lymphogel.

“Surprise: cells taken from the metastasis grew more effectively because they were in the right environment,” Salo explains.

“Now we are conducting research on a culture medium made of human lymph nodes to see whether it works better than the one made of pig lymph nodes. Human tissue is more similar to pig tissue than it is to mouse tissue, so it may be close enough. If not, we’ll have to make a Lymphogel based on human cells.”

Oral cancer research group

Department of oral and maxillofacial diseases, Faculty of Medicine

Doctoral programme in oral sciences

Translational immunology programme

Oral cancers are on the increase, reason unknown

During the last 35 years, the number of oral cancers (link in Finnish only) in Finland has tripled. There has been a particular increase in cases of tongue cancer.

Known risk factors for oral cancers include smoking and heavy alcohol use, but these factors do not explain why these types of cancer have become increasingly common.

“The increase is particularly apparent among young people who do not smoke or use a lot of alcohol. According to observations in the United States, tongue cancer has seen a particular increase among young women. No one knows the reason for this,” says Professor of Oral Pathology Tuula Salo.

Oral cancer can remain relatively symptomless for a long time, but still metastasise at an early stage. The earlier the cancer is detected, the better the prognosis. The mortality rate for oral cancer in Finland is 33–39 per cent within five years of receiving the diagnosis.

“On the other hand, some of the oral cancers diagnosed at an early stage still lead to death, so late diagnosis is not the only factor contributing to poor prognosis,” Salo notes.

Salo’s research group works at the Faculty of Medicine at the University of Helsinki, and also takes part in the Faculty’s Translational Immunology Programme (TRIMM). 

“Our goal is to also develop a personalised approach to treating oral cancer,” Salo concludes.