The evolutionary process of metastasis

The development and growth of a malignant tumour as well as metastasis can be understood and described as evolutionary processes which occur in stages. Two models of the processes have been described. In the so called linear development model, metastasis will only kick in in the late developmental phase of the primary tumour. The parallel evolution model describes a different timing scenario, where the primary malignancy and metastasis develop simultaneously and where various mechanisms of metastasis begin early and continue throughout. The latter model can explain the development over time of metastases with widely varied (genetic) properties and behaviour (see below). Recent research points to a continuum of the two models over time, with a shift between linear and parallel processes taking place over time. However, both models are not very refined because they do not take into account any genetically heterogeneous make-up of a primary tumour or any metastases.

The initiation of a primary malignant tumour is the first ‘learning step’ of normal cells to acquire the potential for unlimited growth, particular survival abilities and some genomic instability (and thus flexibility and adaptability). These new abilities of cells in becoming malignant cells are usually brought about by genetic mutations that often lead to the inactivation of genes that suppress tumour growth. Many of these oncogenic mutations that lead to the establishment of a primary malignancy are well researched and understood, the genetics of the formation and evolution of metastases (and the recurrence of a malignancy) much less so.

Malignant cells of the primary tumour becoming mobile

With the exception of blood cells, the various body organ and tissue cells in mammals (including humans) are stationary and do not travel around the body. In healthy tissues, specific  tissue cells recognise each other by means of messenger molecules on the cell surface and specialised protein molecules on the cell surface act as ‘glue’ to keep the cells of an organ together.

Malignant cells lack some of the surface molecules that keep healthy tissue cells together, so in principle have the ability to be detached from a cohort of malignant cells, that is from a tumour site. The process adopted by malignant cells for this purpose is similar to the mechanisms at work in the development of an embryo or in wound healing (epithelial-mesenchymal transition).

There has to be some driving force for malignant cells to leave their original location and there have to be properties that distinguish the mobile malignant cells from those of a stationary, original tumour. This part of the process is not yet completely understood but there is a large body of ongoing research on this topic. For example, initial suggestions include the implication of a particular gene, p53, that is involved in the regulation of cell death (apoptosis) as well as cell birth (there are thousands of research publications about p53). Ongoing and evolving variability and genomic instability play a role (some small local DNA variations known as copy number variations have attracted attention) – new, genetically slightly altered copies (clones) of malignant cells may simply be programmed to be mobile, or some local and relatively minor genetic variations may favour the development of mobile cells. In addition, the physiological conditions in the tumour tissue may be an important driving factor. In many solid tumours there is insufficient blood supply and consequently, the tumour tissue suffers hypoxia (lack of oxygen supply). This lack of oxygen causes stress for the malignant cells and may be another factor leading to mobilisation of cells from the tissue (interestingly, hypoxia also makes cells more resistant to radiotherapy treatment).

With different primary malignancies developing from different body tissues and cell types, it seems intuitively convincing that different malignant tumours will display a wide range of tendencies for the formation of local and/or distant metastases (as is observed clinically). Patterns of preference for the location of distant metastases (organ tropism) in certain organs, depending on the primary malignancy, in part are explained by anatomical facts, such as the distribution pathways for the spread of metastases (see below).

Malignant cells of the primary tumour having become mobile – distribution channels

In order to travel around the body and possibly start new growth in remote parts of the body (distant metastases), there are two principal distribution channels: the lymphatic system and direct entry into the blood stream (haematogenous route). Entry into the blood stream may also occur via an initial entry into the lymphatic system and further distribution from there. This process usually involves local lymphatic vessels and local or regional lymph nodes.

In order to be able to enter blood or lymphatic vessels, the mobile malignant cells have to acquire further abilities. For example, the travelling cells need to produce certain enzymes (proteinases) that can digest tissue (such as the protective membranes of blood vessels) to enable, or ease, invasion into the blood stream (such abilities also help the primary, stationary tumour to invade adjacent tissue).

The lymphatic system, including the lymph nodes, plays a particularly important role. The normal physiological task of the lymphatic system is to provide protection from infection and all kinds of invasion of the body by foreign agents. The lymphatic fluid carries migrating cells, pathogens and other biological macromolecules to the lymph nodes. The lymph nodes are essentially filter stations, distributed all over the body, where alien agents and pathogens get removed from circulation and are disabled.

For a number of reasons, the lymphatic system is an ideal target for the initial invasion of predominantly local lymph nodes. There tends to be increased pressure in tumour tissue. Accordingly, mobile malignant cells may end up being carried passively into the lymphatic system. In line with its normal physiological role, the lining of the lymphatic system is structured such that it enables permeation by particles. For example, the peripheral lymphatic capillaries have no, or only an incomplete, basement membrane. This also makes it easier for tumour cells to enter the lymphatic system – the mobile malignant cells have to acquire fewer additional abilities than is necessary to enter blood vessels directly. Malignant cells may be travelling as single cells or in small groups of identical or dissimilar clones.

Having said that, it is possible for malignant cells from the primary tumour to directly enter the blood system, if they have the right set of abilities (this is more often seen in connective tissue malignancies (sarcomas) than in epithelial malignancies (carcinomas); melanoma being a malignancy of specialist pigment-producing cells defies categorisation in this way and can do both). Alternatively, once a colony of malignant cells is established in a regional lymph node (see below), these cells can further adapt and acquire the abilities needed to invade the blood stream starting from the lymphatic system. That can be a more efficient mechanism than direct entry into the blood stream: the malignant cells already had to develop a sub-set of abilities to be able to enter the lymphatic system and may only need to acquire a smaller range of additional abilities to move on.

Systemic metastases

Only a small minority of malignant cells that enter the blood or lymphatic system will end up forming metastases: only malignant cells with the ability to replicate can do so (so called tumour stem cells). In addition to this fundamental ability of a cell, it is also necessary for it to have escaped the body’s immune system (often by stealth), to form a bond with tissue in the new location (using ‘glue’ proteins on the cell surface that fit the new environment; by expression of suitable surface markers) and to initiate the formation of a blood supply for the newly growing metastasis (angiogenesis). This is true for the formation of metastases in regional lymph nodes as well as for the formation of distant metastases.

Essentially, the remote colony of malignant cells repeats the process of establishing the primary tumour in a regional or distant new location. If this colony in the distant site arrived there via an intermediate stage as a metastasis in a regional lymph node and entered the blood stream from there, this cohort of malignant cells will likely already have acquired many of the abilities and functions needed to settle and grow a new tumour.

Some organs and tissues are prone to the establishment of metastases, especially liver, lungs and bone marrow. These organs have a particularly rich blood supply, enhancing the chances of migrating malignant cells in the blood stream to travel there, and to get established there. Moreover, recent research has found hints that the primary tumour may be actively involved in the establishment of a new distant colony by shedding small membrane particles which can transport growth factors to the new location, helping the newly arrived malignant cells to establish a new colony.

The genomic instability of a malignant tumour is a pre-requisite to form metastases, and these have similar attributes. New clones of the primary tumour and/or metastases are being formed all the time. The more aggressive and flexible the clone, the higher its success rate will be (until the host is killed by the disease). The Darwinian pressure to evolve explains why many metastases are not genetically identical with the primary tumour: only cells with certain additional abilities were able to migrate, to re-settle and to replicate. Accordingly, therapies that are able to treat the primary tumour may not always be able to treat the metastases. This is especially true when a primary tumour continually produces new metastases. These will show an increasing degree of genetic diversity such that some colonies of metastases become resistant to treatment. The Darwinian evolutionary pressures also explain why many primary tumours themselves are not genetically homogenous. There is much need for research using careful genetic mapping of primary tumours, metastases and, where applicable, recurrent primary tumours: a complete map of the genetic evolution of the intricate systems of primary malignancy and its metastases will eventually help to improve treatment, or even prevent or slow the development of metastases. Despite extremely rapid recent advances in the understanding of the biochemistry of metastasis, there remains a huge body of work to be done. It is so important to clarify all these mechanisms because there are profound implications for the treatment of malignant disease at various stages: take for example a primary malignant tumour which has seeded a metastasis in a regional lymph node and in a distant location. The two metastases may be identical clones of each other, or they may differ. If the local lymph node functions as a gateway for further spread, one can argue that removal of local lymph nodes should diminish further spread. If there is independent haematogenous dissemination without involvement of local or regional lymph nodes, the argument may well be not in favour of clearing the local lymph nodes. Or would such an argument be completely useless if, for example, any micrometastases (see below) established in a local lymph node would not just have the ability to initiate distant metastases, but could also re-seed a new version of the original tumour in its old location (commonly called a recurrence)? There are indeed many questions to investigate and to answer.

Metastasis and head & neck malignancies

Head and neck malignancies have a relatively low tendency for the formation of distant systemic metastases. However, the local and regional lymph system plays a major role in these malignant lesions. This can be understood from some straightforward considerations of anatomy. There are roughly 800 lymph nodes in the human body; about 300 of these are in the head and neck region. The oral cavity and nearby regions have a very dense network of peripheral lymphatic capillaries, connected to multiple lymph nodes in the neck. This makes perfect sense when one thinks about normal body function: with the mouth and nose being the body’s gateway to the outside world, infection prevention and invasion control are especially important in that part of the body. On the other hand, it also means that any oral malignancies reside in a part of the body with particularly rich opportunities for spread to local lymphatics and regional lymph nodes.

From a clinical and pragmatic view this means that the cervical lymph nodes (the lymph nodes in the neck) are of considerable importance. They are part of a response to limit the spread of malignant cells but they also act as a filter and repository of those cells.

This can be clinically obvious; the enlarged nodes can be seen or felt, identifiable on specialist imaging such as ultrasound scans, MRI images or PET/CT scans, or only identifiable after specialist histopathological techniques.

Micrometastases are microscopic deposits of malignant cells (usually squamous cells) identified after a meticulous pathological retrieval of lymph nodes from an operative specimen (one of the various types of neck dissection) and analysed microscopically.

It is often said of head and neck cancer that the presence of a malignant neck node halves the chance of surviving the cancer. This is an unhelpful and inaccurate statement. Unhelpful because it doesn’t influence the choice of treatments and inaccurate because the statement was based on data where a ‘positive’ neck node was one detectable clinically. The truth is, we don’t yet know the significance of micrometastases (see above) and many of the more specialist units have demonstrated far better 5 year survival figures than previously shown.

What is true is that the more advanced the cancer is, the poorer the prognosis is for that particular type of cancer (for example, the prognosis for an advanced squamous cell oral carcinoma in a non-smoking patient whose cancer is driven by an oncogenic HPV (virus infection) infection is much better than a similar stage cancer which is not HPV driven in a patient who smokes).

The involvement of neck lymph nodes implies a more advanced cancer but treatment is still carried out with curative intent.This means that the cancer and its associated draining lymph nodes are either surgically removed or irradiated (or in some cases both). The loss of this large number of lymph nodes does not seem to have any adverse immunological effect but does create to a greater or lesser extent swelling by fluid retention (lymphoedema). There are a number of different ways of removing the lymph nodes.

Overall the treatment of a primary cancer and the regional lymph nodes is part of the treatment package ‘with curative intent’. Once the metastases have spread beyond that region (in the case of head and neck cancer this is essentially below the clavicle) the intention of treatment becomes palliative as there are no currently curative treatments for systemic metastases from oral, oropharyngeal or facial and scalp skin cancers. This does not mean to say that treatment cannot or should not be offered as even radical treatment with palliative intent can help some people, but the balance of harm and benefit changes.

Further reading: Diagnosis