Lung cancer: MTSS1 is a putative marker of tumour progression and metastatic disease
Lung cancer is one of the most common malignant diseases and one of the leading causes of cancer-related deaths worldwide. 90% of all lung cancer cases in men and 80% in women are due to long-term exposure to tobacco smoke. In Germany, around 140 new cases are diagnosed every day, and 50,000 people die of lung cancer every year. PD Dr. Gian Kayser, senior consultant in the Department of Clinical Pathology at Freiburg University Medical Centre, studies the pathogenesis and biology of lung cancer. His aim is to develop new therapies. Kayser and his team have identified the protein MTSS1 as a prognostic factor that can be used to assess the aggressiveness of squamous cell carcinomas before they start to metastasise.
Whether they are transporting fresh air, dust or pathogens, the lungs are in direct contact with the outside world with every breath they take. Lung cancer can develop in all sections of the lung. By far the greatest risk factor is inhaled tobacco smoke; the risk of developing lung cancer increases with the quantity of cigarettes smoked and the length of time a person has smoked. Lung cancer is a complex disease to understand and treat. What makes lung cancer particularly dangerous is that typical symptoms such as chronic hoarseness and coughing up blood appear when the cancer is already at an advanced stage. It is then usually too late for treatment. At the time of diagnosis, nine out of ten people who have sought medical attention have symptoms directly related to the tumour or metastases.
Lung cancer kills more people than breast, prostate and colon cancer put together. The chances of successful treatment depend on the nature and extent of the lung cancer, which includes histological subtypes classified as small-cell lung carcinoma (SCLC) or non-small-cell lung carcinoma (NSCLC). SCLCs are characterised by small tumour cells, an extremely rapid growth rate and a very poor prognosis as they spread relatively quickly into other areas of the body, which prevents them from being surgically removed in their entirety. NSCLCs are more frequent than SCLCs – they account for 85 percent of all lung tumours; although they do not grow as rapidly as SCLCS, they still have a bad prognosis. Aggressiveness and mortality tends to be related to the formation of distant metastases.
Understanding the biology of tumours
The detection of lung cancer at an early stage, i. e. before it has spread to other organs, and the division into subtypes is of great medical value, as this increases the chance of treating the cancer specifically and effectively. Metastases are the most deadly aspects of cancer. When the disease spreads from one organ to another unconnected organ, individual cancer cells leave the original tumour and migrate to other parts of the body via the bloodstream and the lymphatic system. They then multiply in the new organ. "Cancer cells often enter the lymphatic vessels before reaching the lymph nodes, which normally act as filters for cancer cells that have broken away from the primary tumour," says Dr. Gian Kayser whose work centres on the study of lung cancer.
Treatment outcome is particularly good when the tumour can be completely removed surgically in the first of four cancer stages. At this stage, it has not yet spread into other parts of the body. However, the problem is that lung cancer is usually not detected in the early stages, or only detected incidentally in people undergoing chest radiographs for unrelated reasons. The chances of cure and survival decrease rapidly if the cancer has already spread to other organs (distant metastases). Cancer cells that are able to spread into distant body areas, need to acquire several abilities, namely the ability to grow into blood vessels, to survive in isolation from other cells and to multiply in tissues other than the original one. According to the multi-mutation theory, these abilities develop thanks to a number of consecutive genetic modifications that have accumulated over time.
Metastasis suppressor 1 (MTSS1)
Kayser and his team found that necroses and elevated cell division rates reflect a cancer's malignant biological profile, even though post-operative analyses are only able to provide a snapshot of tumour development. The researchers analysed 264 non-small-cell lung carcinomas (NSCLCs) using immunohistochemical methods and found a factor in squamous cell carcinoma (SCC) cells that was expressed before the cells started to form metastases. This factor could potentially be used as a prognostic marker for the aggressiveness of lung tumours and enable appropriate treatment to be initiated at an early stage of cancer development. The protein produced by cancer cells in varying quantities at different stages is called metastasis suppressor 1 (MTSS1). "With this protein, we can see on the molecular level that the tumour has developed further at a time when we are still unable to discern these changes histologically," says Kayser. "MTSS1 could potentially be used as a prognostic marker of metastasis."
The researchers found that early-stage tumour cells produce more MTSS1 proteins than non-neoplastic cells. In addition, MTSS1 expression decreases as the cancer becomes more aggressive and before metastases become visible. The interrelation between downregulation of MTSS1 expression and invasiveness has already been shown for other primary tumours such as oesophageal and cholangiocarcinomas as well as for already established metastases. In the past, high levels of MTSS1 expression were correlated with malignant transformation in melanomas and liver cell carcinomas as the protein was assumed to promote cell proliferation and carcinogenesis.
The upregulation of MTSS1 in cancer cells seems plausible because it is here that many embryonic organogenesis pathways are activated. "Cancer cells seem to regress," says the pathologist. Fewer metastases develop at elevated MTSS1 levels. MTSS1 expression is downregulated once the tumour has established itself, most likely because this improves the cancer cells' motility and invasiveness. "A decrease in MTSS1 expression is associated with advanced tumour stages and metastatic disease, and is therefore a predictor of poor patient survival."
Prognostic tool for stratifying therapy
The effect of MTSS1 in healthy cells is not yet known. It is known that the protein is involved in the organisation of actin filaments, and hence in the development and maintenance of the cytoskeleton. In addition, it appears to enhance the transcription of an effector gene of the Sonic Hedgehog signalling pathway. "This signalling pathway is normally inactive in adults but is switched on in cancer cells," says Kayser. Although not all the details are clear yet, these new findings can already be put to practical use.
Patients diagnosed with lung cancer who have tumour cells with high MTSS1 expression levels, could undergo certain supportive therapies. "If I was able to find out at an early stage whether MTSS1 is still upregulated or has already been downregulated, I would have an idea whether the tumour is aggressive or not," says Kayser. A patient with greatly reduced MTSS1 expression might benefit from chemo- or radiation therapy, which would kill the remaining circulating cells.
At present, patients diagnosed with lung cancer who undergo surgery at an early stage are usually followed up for a certain period of time without undergoing chemotherapy, as "chemotherapy is not a walk in the park, and can also be associated with side effects," Kayser says. He is actively looking for new biomarkers that enable the early assessment of lung cancer aggressiveness, but he also knows that the different lung cancer subtypes have different biological profiles. "Although we are always able to find ways to impact a tumour, we cannot do this for all tumours, only for a small subgroup. However, I am also sure many new discoveries will be made in the not-too-distant future."