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2.3.2 Metastatis and systemic effects Cheat Sheet (DRAFT) by

This is a draft cheat sheet. It is a work in progress and is not finished yet.

Introd­uction to metastasis

One of the hallmarks of malignant tumours is the ability of the cancer cell to spread or “metas­tasize” either to local or distant sites.
Metastases are a highly signif­icant cause of cancer morbidity and are respon­sible for most cancer deaths.
Metastasis is a multi-step process which requires, first that cells have to detach from a primary tumour, secondly invade local tissues, lymphatics or blood vessels, and thirdly re-est­ablish and re-attach once they have spread into distant sites.
Cells break away from the tumour and may expand through local tissues, and blood vessels or lympha­tics.
Tumour cells that spread into lymphatic vessels may become localized in lymph nodes and start to expand and prolif­erate within the lymph node. Eventually the lymphatic system drains into the blood stream, thereby facili­tating metastasis to distant sites via the blood vessels.
An altern­ative method of metastasis is spread directly via the blood stream to metast­asize at distant sites and organs.
For many cancers the develo­pment of metastasis either local or distant, may lead to clinically incurable disease. However, this may depend on the tumour type. Some tumours are much more prone to early metastasis than others.
When a cancer is detected at an early stage, prior to the metast­asis, it can very commonly be treated succes­sfully, either by local irradi­ation or by surgical excision resulting in a complete cure.
However, if the cancer is detected only following metast­ases, in particular blood borne metast­ases, successful treatment and cure is much less common.
The molecular mechanisms which mediate the metastasis of cells from the primary tumour, either by the lymphatics or local blood vessels, remain to be fully deline­ated, however, it is clear that the process of metastasis consists of a series of specific steps, all of which must be sequen­tially and succes­sfully undert­aken.
For a cancer cell to metast­asize it must first shed cells from the primary tumour, which requires that the cancer cell must first detach from the parent tumour.
Secondly, the tumour must escape from the local neighb­ourhood of the primary tumour and establish colonies at distant tissues.
A cell must penetrate and escape across the basal lamina, invade either the draining capillary or the draining lympha­tics, and then must initiate and maintain its own growth and either circulate in the lymphatic system, or the blood vessel system, and then adhere to a new site, develop new blood vessels and start to prolif­erate.
For this to be succes­sfully achieved cancers must be able to survive within the circul­ation. It is probable that only a few cells in the primary tumour survive in the circul­ation. Many cancers invade local and connective tissues and cause problems with local recurr­ences. Much less frequently do cancer cells escape into the circul­ation and manage to seed in new areas, grow and prolif­erate.
The cancer cell’s ability to invade, requires that the cell is able to change its subcel­lular site of attachment and increase its ability to move, i.e. cell motility.
Spread of cancer into the lymphatics or blood vessels also requires degrad­ation of the extrac­ellular matrix, resulting in shedding of cells into the circul­ation either directly, or by the lympha­tics.
The molecular events, which mediate cancer cells’ ability to form distant or local metast­asis, are only recently being charac­terized by use of specific gene profiling studies. These invest­iga­tions have analysed the expression of genes in metastatic versus locally invading tumours.

Steps in the Process of Metastasis

Mechanical factors which regulate deposition

A classical example of a tumour that can develop either local or distant metastasis is breast cancer.
Breast cancer cells may invade either the draining lympha­tics, or the local capill­aries. If breast cancer cells leave the primary tumour by blood vessels, the cancer cells will drain into the venous system to the heart and then to the capillary beds of the lung (see Figure 2 below). Cancer cells that transit the lung enter the systemic arterial circul­ation, where they may be transp­orted to distant sites such as the bone or the liver. Altern­atively breast cancer cells, which invade the local lymphatics of the primary site, may drain to the local lymph node.
The number of draining lymph nodes, which contain cancer, which are present at the time of diagnosis, can be an important factor in predicting long prognosis. Cancer cells trapped in the lymphatics may grow, invade and expand, and the patient may subseq­uently present with enlarged lymph nodes. Cells entering the lymphatic system eventually re-enter the blood circul­ation and the cancer cells are then transp­orted via the blood to distant sites.
Specific mechanical factors may determine the fate of cancer cells after they have left the primary tumour. The site of the primary tumour and its blood flow patterns, which drain the area, may determine in which organ the cancer cells travel to and initially deposit. This may in part explain, for example, that the liver is the primary site of metastasis from colon cancer, however, this does not explain why bone is the primary site for metastasis for breast, or prostate cancer, or why there are often long delays for the appearance of bone metastasis associated with these cancers.
Data from a number of different experi­mental models has supported the idea that specific mechanical factors may regulate the delivery of cancer cells into the capill­aries (see Figure 3.2.4 below). The relative sizes of cancer cells versus the sizes of capill­aries may determine whether the cells arrest, or are effici­ently transl­ocated into the circul­ation. Secondly, it is becoming increa­singly apparent that certain organs will prefer­ent­ially either support, or suppress the growth of specific cancer cell types. This may contribute to whether a circul­ating cancer cell has the ability to deposit in a specific organ. It is noteworthy that both the lung and liver are extremely efficient in stopping the flow of cancer cells. This may relate to the size of the circul­ating cancer cells compared to the size of the capill­aries in both these organs, which both contain many capill­aries of small size approx­imately between 3 to 8 micron in diameter. These capill­aries are designed to facilitate red blood cell passage, which are 7 microns in diameter, but as cancer cells are much larger at 20 microns, the cancer cells are prone to arrest. Arrested cancer cells may undergo adhesion in the precap­illary vessels such as portav­enules in the liver, and once adhered start to prolif­erate to form single or multiple metastatic deposits

Cancer and normal cells arrest in the circul­ation

The Regulation of Metastatic Growth

Factors, which are secreted or localized in specific organs, can determine whether or not a cancer will grow at that site.
For example, one of the reasons why breast or prostate cancer may grow specif­ically in bone may relate to the presence of local hormones or cytokines, which are secreted or present in the bone matrix, which stimulate the growth of the cancer cell.
These molecules include parath­yroid hormon­e-r­elated protein (PTHRP) and transf­orm­ing­-growth factor b, which are produced by the cancer cells, or are present in the bone enviro­nment.
Factors that are specific for the liver have also been identi­fied, such as epidermal growth factor receptor, and transf­orming growth factor α.
Another gene that has recently been shown to contribute to liver metastasis is the Ras gene. Ras is a small GTP-bi­nding protein that amplifies intrac­ellular signals generated by growth factors.
Ras is commonly mutated in many types of human cancers. Recent studies have shown that cancer micro-­met­astases occurring in the presence of activated Ras, are much more likely to maintain metastatic growth, than cancers without Ras mutations.
Therefore, the ability of the cancer cell to grow in a specific organ depends both on the enviro­nmental factors and cytokines present at that site, the size of the capill­aries, the hormones and cytokines synthe­sized in specific tissues, and also depends on the cancer cell itself, whether it has the ability, size, mechanical features and the genetic defects within its genome which facilitate metast­asis.

Cancer dormancy

Metastases can occur long after the initial excision of the primary tumour. Breast cancer and melanoma patients may develop distant metast­ases, decades after the excision of the primary tumour.
The molecular mechanisms mediating cancer dormancy are unknown, but it is unlikely that it is mediated by continuous slow growth, and more probable that the cancer cell undergoes a period of quiesc­ence, and then for reasons unknown its growth is reacti­vated.
Cancer dormancy is of clinical importance because if we could identify what regulates cancer dormancy this may be important in terms of therap­eutic treatments and response to radiot­herapy.
Several studies have suggested that dormancy may relate to the failure of micro-­met­astasis to develop their own blood vessels. Therefore, the tumour may survive, but cannot expand, because it cannot increase its blood supply.
If these metastases subseq­uently acquire their own vascular circul­ation, they may begin to grow and the metastasis may become clinically evident.
An altern­ative possib­ility is that solitary cancer cells seed in secondary site, but do not prolif­erate. These cells may persist for long periods of time without prolif­erating until later times when, for unknown reasons, these dormant cells may start to prolif­erate.
Any therapy that has the ability to inhibit the growth and metastasis of cancer cells and limit damage is of clinical import­ance.
Recent studies have highli­ghted the develo­pment of a novel anti-m­eta­stasis therapy, firstly by identi­fying genes that have been mutated in the cancer cell, which facilitate metast­asis, and also by attacking specific targets such as micro-­met­astases that require vascul­ari­zation.
Current novel anti-a­ngi­ogenic (i.e. targeting new blood vessel formation by the cancer) strategies are becoming of increasing import­ance, as this may regulate the growth and vascul­ari­zation of metast­ases.

Lymphatic metastases

A common site for cancers to spread is the draining regional lymph nodes. The molecular mechanisms that facilitate lymphatic spread are unclear. In addition, the role of lympha­ngi­oge­nesis i.e., the growth of new lymphatics is currently being determ­ined.
Recent clinical and experi­mental results have identified specific lympha­ngi­ogenic factors may play a role in the spread of tumours.
Lympha­ngi­ogenic growth factors include vascular and epithelial growth factor VEGFC, and VEGFD and their receptors on the endoth­elium. These specific endoth­elial growth factors are secreted as pro-pe­ptides and are subseq­uently cleaved by proteo­lysis to form a high infinity ligands that activate their specific receptor and result in the formation of new lymphatic vessels.
VEGFC and VEGFD are growth factors that are synthe­sized by a signif­icant number of cells and tissues during embryonic life and adult life. These two growth factors bind specific receptors VEGFR2 and VEGFR3. Activation of the VEGFR3 receptor causes lympha­ngi­oge­nesis, (formation of new lympha­tics).
In contrast activation or ligand binding of VEGFR2 promotes a formation of new blood vessels (angio­gen­esis).
Both VEGFC and VEGFD can induce tumour lympha­ngi­oge­nesis and specif­ically direct metastasis into the lymphatic vessels and lymph nodes. Thus these factors may thereby promote the lymphatic spread of human tumours.

Lympho­edema (arm swelling)

One of the signif­icant compli­cations of cancer spread to lymphatic vessels is lymphatic obstru­ction.
As the lymphatics control the pressure of the inters­titial fluid in tissues, the lymphatics transport excess fluid via the lymphatics to eventually return to the venous circul­ation.
One of the serious compli­cations of metastatic spread to lymph nodes and lymphatic vessels is the blockage of the vessels by the metastatic tumour.
Oedema is a clinical situation in which swelling develops resulting from blockage of the lymphatic system. This may be a result of impaired lymphatic drainage, due to either inflam­matory or cancer mediated obstru­ction of the lymphatic vessels.
When this occurs due to blockage of the peritoneal drainage, or peritoneal seeding of cancer with cancer cells, this may result in a clinical situation of “ascites”, which is the accumu­lation of fluid in the peritoneal cavity.
In addition, oedema may follow surgical removal of lymphatic vessels or radiot­herapy for breast cancer, resulting in arm oedema “lymph­oed­ema”.
The current treatment for lympho­edema is by manual lymphatic drainage by compre­ssion.

Angiog­enesis

An essential requir­ement for tumour growth and metastasis is the formation of new blood vessels (angiog­enesis).
As many tumours are rapidly growing, they need to be able to develop ability to provide their own blood supply via the formation of new blood vessels.
Correl­ations have been shown between patient survival, and the number and degree of vascul­ari­zation of specific tumour types. A high degree of tumour vascul­ari­zation may be associated with an increased incidence of tumour metast­asis.
The formation of new blood vessels requires the generation and prolif­eration of endoth­elial cells, which line the blood vessels, the break down of the extrac­ellular matrix and the migration of endoth­elial cells.
Specific growth factors such as vascul­oen­dot­helial growth factor, heparin binding growth factor, and vascular permea­bility growth factor, promote the formation of new blood vessels and as a conseq­uence tumour growth.
Angiog­enesis has been recognized as a potential target in the treatment of cancer and a number of inhibitors of angiog­enesis have been identified and are being currently developed as potential therap­eutic strate­gies.
Such molecules include “Angio­sta­tin”, which is a 38 kilodalton fragment of the plasma protein plasmi­nogen, which has the capacity to suppress the growth of metast­asis.
Other methods that are used to control vascul­ari­zation of tumours include, in certain tumours, the tying off of the blood vessels that supply to the tumour. This depends on the nature of the tumour and has only limited potential as a treatment strategy.

Metastasis to specific sites – Bones

Patients with breast and prostate cancers very commonly develop bone metast­asis.
In many instances the patients do not die of cancer at the original or primary site, but rather as a conseq­uence of the metastatic tumour burden, or compli­cat­ions.
Bone metastasis often occurs in cancers, which do not necess­arily have a primary aggressive tumour. Metastasis to bone may cause severe unrele­nting bone pain, which causes major patient morbidity.
The physio­logical mechanisms mediating this severe bone pain are unclear. Recent treatment strategies using inhibitors of bone reabso­rption have shown promise in terms of relief of bone pain; these include the use of osteop­rot­egrin (OPG), or the bispho­sph­onates.
The latter has now become standard treatment for the treatment of osteop­orosis and/or osteolytic lesions associated with diseases such as multiple myeloma. Sites for bone metastases include the load bearing bones, the neck of the femur, or in the vertebra, which may lead to weakening of the bones, resulting in pathol­ogical fractures. Other side effects of a bone metastasis include nerve compre­ssion, spinal cord compre­ssion as a result of vertebral body collapse. Increases in the serum calcium (hyper­cal­cemia) and bone deformity may also complicate bone metast­asis.
The effect that the bone metastasis has on the bone will depend on the type of cancer.
In tumours such as breast cancer and multiple myeloma destru­ction of bone resulting from lytic lesions within the bone, know as “osteo­lysis” occur. In contrast some tumours, in partic­ular, prostate cancer, may lead to increased synthesis of bone, or “osteo­bla­stic” changes to the bone.
In a latter condition, the osteob­lastic lesions results from a synthesis of specific growth factors such as platelet derived growth factor, or endoth­elium1, which promote new bone formation.
Lytic lesions in the bone, such as those observed in breast cancer are commonly caused by synthesis of parath­yroid hormone related peptide (PTHRP), which leads to increased bone resorption (process by which osteoc­lasts break down the tissue in bones and release the minerals).
Treatment of patients with phosph­onates may block bone resorp­tion.
Bispho­sph­onates are pyroph­osphate analogues, which bind with high affinity to minera­lised bone surfaces and thereby inhibit the action of bone cells known as osteoc­lasts which mediate bone resorp­tion.

Physical effects of cancer on the patient

The effects of cancer on the patient can be local or systemic, and may also be specific for particular tumour types.
The physical presence of a tumour can cause major problems when the tumour displaces normal tissue leading to reduced organ function.
The tumour may expand into surrou­nding areas leading to venous or nerve compre­ssion, or may cause blockage of vital passages.
The displa­cement of normal tissue in contained spaces such as the brain by cancer causes increased pressure not only resulting in pain, but also decreases in brain function.
Cancer cells replace normal brain cells, however they do not carry out the function of normal brain cells as they are in an undiff­ere­ntiated immature form, resulting in reduced function.
The growth of a tumour can block a vital organ or passage.
For example colon cancers may grow to a signif­icant extent locally so they block the bowel and lead to bowel obstru­ction in the absence of distant metast­asis. In addition tumours may block the normal arterial supply, or venous or lymphatic drainage of tissues or organs leading to signif­icant symptoms.
Cancer also causes nutrit­ional problems in the patient, partic­ularly in cases when the cancer has dissem­inated, and is often associated with nausea and weight loss.
Changes to tissue metabolism results from the presence of the rapidly prolif­erating cancer cells, and the secretion of factors such as tumour necrosis factor, interl­eukins and other cytokines and hormones by malignant cells into the surrou­nding tissue.
The secretion of these factors can alter tissue metabolism leading to protein metabo­lism, glucose intole­rance, and breakdown of fats.
The breakdown of protein and fats provides the tumour with a sufficient energy source to maintain the high metabolic rate required for successive rounds of cell division.
The high energy consum­ption by the tumour leads to general weight loss, fatigue, cachexia and suscep­tib­ility to infections in the patient.
Cachexia is a profound weight loss associated with cancer, or other disease state.
While cancer is respon­sible for varying degrees of pain and nausea in the patient, various treatments are often respon­sible for a signif­icant amount of patient discom­fort. Radiation or surgical procedures are pain associ­ated, together with the toxic effects of chemot­herapy. Nausea suffered by a cancer patient is most commonly caused by chemot­her­apeutic treatment, the cancer itself or medica­tions such as antibi­otics.

Why people die from cancer

The most common cause of cancer induced death is from metastatic lesions to the liver, brain or bone, or lung, which block a vital passage, or destroy the function of a vital organ.
In brain cancers, patients may not develop metastases but may die from raised intrac­ranial pressure, as the tumour continues to grow in the confined space of the brain within the skull.
Patients with metastatic tumours lose weight, have decreased mobility and increased suscep­tib­ility to infection. Patients die from the successive accumu­lation of these insults.