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Dr. Ali Al-Bayati

 
Most of the site will reflect the ongoing surgical activity of Prof. Munir Elias MD., PhD. with brief slides and weekly activity. For reference to the academic and theoretical part, you are welcome to visit  neurosurgery.tv

 

The staging of cancer and its treatment are dependent on the presence or absence of metastases. The specific clinical details and the biology of metastases vary with the site and extent of target organ involvement and with the nature of the primary cancer. The picture is complicated by individual variations in host response and anatomy and by the natural history of the metastatic process as modified by treatment.

The metastatic cascade consists of a number of exceptionally complex, overlapping, repetitive steps. The first phase is concerned with invasion and ultimately involves the entry of cancer cells into blood, lymph, and cerebrospinal fluid as well as various body spaces and cavities. The second phase of dissemination involves the transport of cells that have gained access to the various disseminative channels and their arrest at target sites. Most of the arrested cells are killed. The comparatively few viable cells retained in the target organs develop into micrometastases, which in themselves are relatively harmless. However, as a result of cancer-host interactions, including neovascularisation, the micrometastases may enter a growth phase and develop into metastases. A major clinical problem is the detection of micrometastases and the prevention of their development. The final step in the cascade is the metastasis of the metastases.

A major problem in determining the mechanisms involved in metastasis is obtaining suitable animal models. Although the genetics and immunology of mouse tumor systems are well documented, the short life span and hemodynamics of the mouse make it in some respects an unsuitable model. In larger animals, although their life spans and hemodynamics are more relevant to the human situation, the genetic uncertainties, problems in obtaining transplantable cancers, and practical difficulties associated with procuring large animals with spontaneous tumors make it difficult to perform reproducible experiments. No experimental system provides a total model for human metastasis, but judicious studies with these systems provide useful information on parts of this disease process. The development of noninvasive techniques will, it may be hoped, permit the ethical study of metastasis in humans.

Cell Detachment from the Primary Cancer

Detachment is an essential part of the metastatic process, because by definition, a metastasis is a cancer that has lost contiguity with the tumor generating it. The suggestion that the undeniable tendency of cancer cells to detach from their parent tumors is an inherent part of the malignant phenotype is a misleading simplification, because it focuses exclusively on hypothetical stable cancer specific properties of the cancer cells themselves. Cell detachment is not cancer-specific, and although normal tissues do not metastasize, it must be emphasized that detachment is not synonymous with metastasis. The relative ease with which cancer cells detach from tumors varies not only with the pathophysiologic status of the malignant cells themselves but also with the dynamic properties of the whole tumor, which contains cancer and noncancer cells, both modified by host response.

Factors Affecting Detachment

Many tumors exhibit considerable heterogeneity, not only with respect to the cancer cells that they contain, but also with respect to regions of proliferation and necrosis, host cell infiltration, fibrosis, encapsulation, and blood supply. The effects of some of these variables on cell detachment have been quantitated by various techniques in which cultured cells are detached from their substrata by known hydrodynamic forces or are shaken free of small blocks of tissues under carefully standardized conditions.

Growth Rate

A number of experiments made with cancer and noncancer cells have revealed that the higher the growth rate the more easily the cells are detached from one another and from artificial substrates. As cell detachment is only an initial step in a complex series, it is unlikely that correlations could be demonstrated between tumor growth rate, detachment, and metastasis over the whole range of cancers, where so many other variables come into play. Attempts to correlate growth rate with metastasis reveal many apparent contradictions, such as rapidly growing tumors that do not metastasize and slow-growing tumors that do; the problems of occult primary cancers are well known. However, in a number of palpable human epitheliomas in which growth rate could be assessed by size change measured with callipers, Gliicksmann reported a striking correlation between growth coefficient and the incidence of local lymph node metastasis.

Necrosis

Necrosis is a common feature of solid tumors, as a consequence of growth-associated vascular insufficiency, host-defence reactions, and therapeutic intervention. In studies on W256 tumors, regions of central necrosis developed in tumors exceeding 1 cm in diameter. It was shown that viable cancer cells were more readily detached from each other in the juxtanecrotic regions than in the more peripheral regions of tumors. This effect was mimicked by exposing samples from the tumor peripheries to saline extracts of the necrotic core. When W256 tumors grow in the rat liver, the parenchymal cells close to the tumor edges may be more easily separated from each other than those located 0.5 or 1 cm from the tumor periphery. The evidence suggested that the necrotic material acted as a pool of free lysosomal enzymes and other material that acted on the various cells present in the tumors and facilitated their detachment by direct or indirect mechanisms.

Whether the demonstrable necrosis-associated facilitation of detachment actually promotes metastasis depends on whether the released cancer cells are free to disseminate. On the one hand, the facilitated detachment of cells in the tissues surrounding a tumor is reasonably expected to promote its invasion, particularly as necrotic extracts promote the active movements of some types of cancer cells. On the other hand, if necrosis results from vascular insufficiency, immediate dissemination of detached cancer cells may not occur. Depending on the accessibility of cancer cell' 'escape routes," there is the possibility that by causing necrosis in the absence of a 100 percent kill, local therapy may actually promote dissemination. In this connection it is of interest that exposure of cancer cells to a variety of antimetabolites promotes their detachment in vitro.

Enzymes

Many pathologic processes associated with inflammation, immune response, therapy, etc. that result from the release of free radicals are ultimately expressed in enzyme release; in events related to metastasis, the enzymes may be derived from the cancer cells themselves, from vascular endothelial cells, from other cells of the reticuloendothelial system, and from other types of cell. It has been known for many years that viable cells may be liberated from a variety of tissues by the action of enzymes combined with the application of distractive forces generated by muscle movements, surgical trauma, etc. In essence, free enzymes may facilitate cell detachment by lysis of intercellular material. In addition, the release of endogenous enzymes by both cancer cells and nonmalignant "bystanders" also facilitates detachment. The Iysosomes constitute an obvious and well-documented nonexclusive source of such enzymes, and a large number of factors activating Iysosomes promote detachment, whereas a number of agents stabilizing Iysosomes inhibit the process, as do enzyme inhibitors, including the tissue inhibitors of metalloproteinases (TlMPs).

Stress

Although the effects of surgical manipulation on cancer cell release are well documented, it is not generally appreciated that the appearance of malignant cells in the bloodstream and the release of cells from tissues can be promoted by stress and anaesthesia. These disquieting phenomena are worthy of further study.

Cell Movement and Invasion

Cell movement may be active or passive. In invasive processes, cancer cells may crawl through tissues and breach basement membranes during intravasation and extravasation. Alternatively. invasion may result from the expansive forces generated by growing tumors (vis a tergo), and movement will occur along the paths of least mechanical resistance. Expansion by growth can result in arrested tumor emboli bursting out of blood vessels. Although active movement of cancer cells was recognized by Virchow in 1863, for various technical reasons the relative importance of crawling and growth-associated expansive movements were never quantitatively assessed until recently. A technique has been developed in which, from statistical analyses of cancer cell density counts made on tumor sections, the diffusive density patterns associated with active cell movement may be discriminated from the more abrupt patterns associated with growth. Tests of the technique made on sections of malignant melanomas in human skin confirm the validity of the technique and indicate that actively moving melanoma cells invade the dermis to a depth of up to 500µm in advance of the main tumor body. Within this zone. it appears that the cancer cells stop migrating and proliferate. The whole process is then repeated. This progression of invasion in 500 µm steps suggests reappraisal of wide-margin excision protocols for cutaneous melanomas.

For active locomotion to occur, cancer cells must first make contact with and adhere to tissues through which they move; locomotor energy generated by the cell acts on these adhesive regions, and finally, localized detachment must occur to permit translatory movements. Therefore, agents promoting initial cell adhesion and cell detachment and stimulating the actin-containing contractile microfilaments in cancer cells are expected to promote active movements and vice versa. Enzymes are expected to have paradoxical effects, because they may inhibit the formation of focal adhesions or destroy them and may also promote detachment. The action of any agent will probably depend on its effects on a rather delicate balance of the three basic components of active movement.

In invasion, the degradation of tissue matrix and basement membranes is effected by four types of proteases, namely (1) metalloproteases (e.g., collagenases); (2) cysteine proteinases (e.g., cathepsins B,D,L); (3) serine protease plasmin; and (4) plasminogen activators. In general, these enzymes are produced by leukocytes, fibroblasts, endothelial cells, and cancer cells.

The urokinase-type plasminogen activator converts plasminogen into plasmin, which brings about pericellular proteolysis. Although initially secreted as inactive proenzyme (pro-uPA), it is activated by binding to a specific receptor (uPA-R) at the surfaces of cancer and noncancer cells. In addition to direct proteolysis of tissue matrix elements (e.g., fibrin, laminin, fibronectin, proteoglycans), plasmin converts procollagenase type IV into active collagenase IV, which degrades collagen IV, the major structural component of basement membranes. Degraded collagen stimulates cancer cell migration. Naturally occurring plasminogen activator inhibitors (PAIs) fall into two groups; PAI-1 and PAI-2 belong to the serpin superfamily, and PAI-3 is the protease nexin. Preliminary results indicate that in breast cancer, expression of uPA and PAl-1 antigens are independent prognostic factors for relapse-free survival, and multivariate analysis reveals that breast cancers exhibiting high uPA and high PAl-1 levels are associated with high risk for relapse regardless of lymph node involvement. This interesting observation will doubtless be tested further. Receptor­mediated internalization of the uPA/PAI-1 complex may also trigger cell proliferation, illustrating coupling between the metastatic process per se, and cancer cell proliferation.

In addition to these effects, enzymes, by acting on the noncancerous tissues surrounding a tumor, may facilitate movement by expansion. In contrast, by destroying the substrate through which a cell could move and thus preventing adhesion, enzyme-related tissue lysis could also prevent or inhibit active movements of cancer cells and make inactive movement by tumor expansion (vis a tergo) more important in this phase of metastasis.

Circulating Cancer Cells

Cancer cells may gain direct access to the venous circulation, or alternatively may gain access first to the lymphatic system and then to the bloodstream. There are so many communications between the lymphatic and venous systems that except in the earliest stages of metastatic cancer, it seems unrealistic to consider metastasis as being limited to one system or the other. This view should not be confused with the question of the desirability of lymph node removal in the treatment of early cancers, because this has the double function of permitting accurate TNM staging and the eradication of potential generalizing sites.

The observation that in the early phases of clinical disease, sarcomas tend to give rise to haematogenous metastases whereas carcinomas generate lymphogenous metastases, has given rise to the commonly accepted concept that carcinomas disseminate via the lymphatics and sarcomas via the blood. The evidence is that lymph node metastases are approximately three times as common in carcinomas as in sarcomas, which does not make lymphogenous metastasis of sarcomas rare, and the postregional lymph node pattern of metastasis from carcinomas is frequently haematogenous. The initial disseminative route is to some extent influenced by the site of cell detachment from the primary lesion. If detachment occurs prior to contact between the tumor and blood channels, as in the case of early cutaneous melanomas, for example, where cancer cells actively locomote through the dermis, they will have the opportunity to gain early access to the lymphatic system. If contact with blood channels occurs prior to detachment, venous dissemination will be the preferred initial route. If parts of an invasive tumor project into the lumen of a blood vessel, cells can be detached by a combination of factors described above. An alternative mode of entry takes place in some sarcomas, where vascular clefts lined by cancer cells are present and shedding is directly into the bloodstream.

Comparisons between sarcomas and carcinomas, disregarding disease status, are incorrect because carcinomas metastasize via both the blood and lymphatics, and lymph node involvement may be detected at an earlier stage than small haematogenous metastases in other organs. Alternatively, carcinoma cells may initially disseminate synchronously via both routes, but the posthaematogenous delivery phase in the microvascular beds of organs may take place in a more hostile environment for carcinoma cells than lymph nodes; the converse may be true for sarcomas. Therefore, differential metastatic patterns between the two classes of tumors depend not only on factors governing entry into, and delivery via, the different routes, but also on differential interactions in the post delivery phase of disease.

Any quantitative assessment of haematogenous metastasis requires knowledge of the numbers of cancer cells entering the bloodstream. Much of the earlier literature on the occurrence of circulating cancer cells in people is suspect because in a number of papers, megakaryocytes and degenerate cells were erroneously described as cancer cells. However, reports of positive identification of cancer cells in the venous effluents of many tumors clearly indicate that large numbers enter the bloodstream, although quantitation is sparse.

The rates of entry of cancer cells into the bloodstream from primary cancers of known size was determined in patients with renal carcinomas, by collecting blood directly from the renal vein just prior to nephrectomy. Cells were released at rates of millions per day, probably for some time before nephrectomy. Two patients in this study were of particular interest: the first had a primary renal tumor, 10 cm in diameter, that was releasing cancer cells at a rate of 5 x 109 per 24 h; and the second had a 6-cm-diameter tumor that released cells at rate of 2.3 x 108 per 24 h. Neither had detectable metastases after 66 and 31 months, respectively, indicating a level of metastatic inefficiency of substantially less than 109; that is, more than 109 renal carcinoma cells have to be released into the renal vein to generate one haematogenous metastasis in the lungs.

On the reasonable assumption that millions of viable cancer cells are liberated into the blood of patients with cancer, then because overt metastases usually occur with frequencies that are orders of magnitude less, one is forced to conclude that in terms of the cancer cells involved, metastasis is a remarkably inefficient process. The mechanisms and implications of "metastatic inefficiency," which is the driving force underlying metachronous (sequential) metastatic pattern formation, is reviewed elsewhere. It is paradoxical that an inefficient process should result in the deaths of so many patients! However, even an inefficient process, will succeed if repeated often enough.

By all accounts, the circulation is a hostile environment for cancer cells; the vast majority perish around the time of arrest in the microcirculation. Part of the circulatory trauma appears to be due to the mechanical deformation imposed on cancer cells in passing through the microcirculation, where they undergo shape transformation from spheres to cylindroids, resulting in stretching and lethal rupture of their external membranes.

Arrest of Circulating Cancer Cells

Without arrest, metastasis cannot occur. Cancer cells are arrested in the microvasculature; single cancer cells in capillaries, and clumps of cells in larger vessels. From an analytic approach, it is important to discriminate between mechanical trapping of cells, which is in a sense independent of local chemistry, and adhesion, which involves chemical bonding between .cancer cells and luminal endothelium and/or subendothelium. It is useful to regard trapping, which brings the arrested cancer cells into close proximity with vessel walls, as the initial event followed by bond formation involving so-called cell adhesion molecules (CAMs).

The surfaces of all types of human cells carry a net negative electric charge. This results in an average electrostatic repulsion between cancer cells and vascular endothelial cells, which tends to prevent their contact and adhesion. The charged groups on a number of cells tend to be arranged in clusters, and in some cells contact is made via fine probes or macromolecules and those surface regions between the clusters, where the charge density is low.

Another factor inhibiting contact relates to fluid displacement from between the vascular endothelium and approaching cancer cells. When a cancer cell moves in the blood, hydrodynamic forces are generated that cause pressure changes and plasma movements close to its surface. This hydrodynamic field is significantly perturbed when the distance separating the cancer cell from the vascular endothelium is less than the cancer cell radius, leading to retardation in contact and hence cell arrest. If the cancer cells are deformed in the contact-making process, so that the cancer cell is flattened to match the contours of the opposing endothelium, the average distance between the two surfaces will be decreased and contact and arrest will take longer.

Another interaction of cancer cell emboli and the vascular endothelium involves embolic size. Single cancer cells are temporarily arrested at the level of capillaries and postcapillary venules, whereas multicellular emboli tend to be shunted through larger vessels where they are either eventually arrested or die in the circulation. In arrested multicellular emboli, the outer cells tend to protect the innermost cells. These and possibly other factors lead to a greater metastatic efficiency of multicellular than of unicellular emboli.

The observation that cancer cells are arrested immediately on entering capillaries, in spite of undoubted electrostatic and viscosity barriers, tends to favor a mechanical trapping mechanism due to both the disparity between the cancer cell and capillary diameters and the irregularities in their surfaces-a Velcro-like phenomenon.

Following cancer cell arrest, the vascular endothelium retracts, exposing the subendothelial basement membrane, which is rich in adhesive molecules associated with the extracellular matrix (ECM). These molecules bind to receptors on the cancer cell surface; one major class of receptors is the integrin superfamily of heterodimers, which bind various ECM proteins, including fibro­nectin [and other proteins containing arginine-aspartate-glycine (RGD) or leucine-aspartate-valine (LDV) sequences], laminin, collagen IV, and fibrinogen. Other CAMs include the selectins, cadherins, and immunoglobulin supergene family (which includes carcinoembryonic antigen, CEA).

Although these CAMs play an important role in the arrest of leukocytes in the microvasculature, this may not be their primary role in metastasis. Many if not all of these molecules have trans­membrane domains, and their primary role may be in signal transduction, utilizing G-proteins, in which signals from the ECM stimulate the reproduction of trapped cancer cells.

Thrombosis and Cancer Cell Arrest

Fibrin and platelet deposition is often seen associated with arrested cancer cells, particularly where there is a defect in the vascular endothelium revealing the underlying basement membrane. Studies by the author and his associates in mice revealed no changes in the arrest patterns of several types of intravenously injected cancer cells when the platelet release reaction was depressed by the administration of aspirin. In addition, therapeutic doses of heparin and warfarin, which affect different levels of the coagulation cascade, were also without effect on cancer cell arrest patterns in both normal mice and tumor-bearing animals with the coagulopathies typically associated with cancer. These experiments suggest that coagulation factors do not playa key role in cancer cell arrest.

From the foregoing, one would expect that a fibrin cocoon provides temporary protection to arrested cancer cell emboli. It therefore seems paradoxical that cancer cells exhibit differing degrees of plasminogen activation; the resulting fibrinolysis would be expected to reduce their metastatic potential.

In view of the association of platelets and fibrin with the metastatic process, there have been many attempts to utilize anticoagulants in antimetastatic therapy. Although the reports of these attempts are both conflicting and confusing, it appears that under certain conditions anticoagulants can reduce the incidence of metastases. However, this anti metastatic effect may not be due to their anticoagulant activity. For example, aspirin interferes with prostaglandin biosynthesis, and warfarin can inhibit cell motility. Another complicating factor is that some agents, for example aspirin, seem to have differential activity on platelets and on vascular endothelial cells.

A physiologic role of the vascular endothelium is to maintain vascular integrity by means of self-purging mechanisms. In situations where thrombi involving platelets are concerned, there is a delicate intravascular balance between the activities of thromboxane Az (TXAz), which aggregates platelets as part of host defence, and prostacyclin (PGIz), which is released by the vascular endothelium and which inhibits TXA2-induced platelet aggregation. The PGIrTXA2 balance is disturbed in the presence of some cancer cells in favor of TXAr-induced platelet aggregation, which is thought to promote metastasis. On this basis, Honn and colleagues have administered agents either promoting PGI2 activity or synthesis or inhibiting TXA2 synthesis to mice injected with cancer cells or bearing tumors and have demonstrated antimetastatic activity. Regardless of whether this form of therapy proves applicable to humans, the observations serve to illustrate the importance in metastasis of interactions involving the vascular endothelium.

The Role of Immune and Inflammatory Responses

The retention of cancer cells by the vascular endothelium may be modified by the immune response associated with tumor bearing. It has been shown that following sensitization, retention of injected cancer cells in the lungs is increased in some tumor-host situations; in others it is decreased, and in others not changed at all. Retention may also be modified by the inflammatory response. For example, in mice, inflammatory reactions in the lungs following bleomycin therapy increase pulmonary retention of circulating cancer cells.

The reticuloendothelial system (RES), which includes the mo­bile and sessile mononuclear phagocytes, leukocytes, and vascular endothelial cells, also participates in the loss of arrested cancer cells. This is indicated by studies in which stimulation of the RES by glucan, BCG, Corynebacterium parvum, endotoxin, and zymosan was associated with increased clearance, whereas inhibition of the RES by silica and trypan blue was associated with reduced clearance. It seems on balance that although the inflammatory response kills tumor cells, the tissue degradation resulting from it facilitates the invasion of the survivors.

Further Development of Metastases

Cells retained in the vasculature of an organ extravasate at an early stage in metastasis development. Extravasation can occur if cancer cells actively migrate through vessel walls, or alternatively, growing emboli can burst out. Both these processes would presumably be aided by enzyme-mediated lysis of basement membranes and the weakening associated with increases in vascular permeability. In addition, the interaction of arrested cancer cells with microvessel endothelium and basement membrane, mediated by adhesion molecules and signal transduction, probably results in expansive intravascular growth of the cancer emboli, thereby promoting a "bursting-out" mechanism of extravasation.

Although the developing metastasis is less than approximately 2 mm in diameter, it can obtain its nutrition by diffusion processes. This provides a functional definition of a micrometastasis, because the increase in size of a micrometastasis to a metastasis requires vascularisation. This is achieved by diffusion of angiogenic factors from cancer cells and other involved tissues and cells to local host capillaries; the endothelial cells are stimulated into mitosis and grow toward and invade the tumor, ensuring its nutrition and growth. The role of neovascularisation is emphasized by experiments showing that agents such as cartilage inhibit tumor growth by inhibition of angiogenesis. Angiogenic factors are not specific for cancer cells but may also be produced by inflammatory cells and fibroblasts. It seems likely that an important component in the neovascularisation cascade is prostaglandin E1. It is therefore of interest that prostaglandin E (PGE) production is one of a number of factors involved in the failure of the immune system to eliminate tumor growth; although immune stimulation results in enhanced PGE production, the prostaglandins produced inhibit function by a negative feedback mechanism.

Failure of micrometastases to grow is associated with the so-called dormant state, which is well recognized by clinicians. In this condition, patients with removed primary cancers survive for long periods with no overt metastases. In apparent response to apparently trivial stimuli they then develop a metastatic "explosion." When recurrence or new cancers are ruled out, the dormant state may represent true dormancy, in which micrometastases behave in an inert manner, with their constituent cancer cells apparently in the nondividing (Go) state. Alternatively, the situation may represent a pseudodormant state in which cancer cell multiplication is balanced by loss. Either way, if by definition micrometastases are not vascularised, it is not difficult to understand their unresponsiveness to systemic chemotherapy. The various complex interactions of cancer cells and the microvasculature are pivotal to the process of metastasis.

Metastatic Patterns

A final step in the development of the metastatic process is the metastasis of metastases. It appears that most human cancers metastasize to so-called generalizing sites, determined by anatomical considerations, the commonest being lymph nodes, lung, and liver. From these secondary sites, tertiary metastases occur. The consequent metastatic patterns depend partially on "mechanical" factors, including target organ blood flow, and partially on as yet undefined "seed and soil" factors. The elucidation of the mechanisms of pattern formation in humans is rendered exceptionally difficult by the perturbations induced by therapy.

Anatomic considerations dictate disseminative routes for cancer cells, and constitute one important factor in determining metastatic patterns. Thus, the initial sites of metastasis are for the most part determined by venous drainage; gastrointestinal tumors metastasize first to the liver via the portal vein, cancers draining into systemic veins metastasize first to the lungs via the venae cavae, and pelvic tumors disseminate in part via the paravertebral venous plexus.

Taking colorectal carcinoma as an example, the clinically important question is whether or not a proportion of the cancer cells entering the liver via the portal vein, leave via the hepatic vein to seed the lungs and a proportion of those pass through the lungs to seed other organs via the arterial route On the one hand, if this synchronous seeding sequence occurs, then providing that enough cancer cells pass through the liver to generate lung metastases, and enough pass through the lungs to generate arterial metastases, the presence of detectable liver metastases would invariably indicate the presence of metastases or micrometastases in the lungs and other organs. This would rule out curative local therapy.

On the other hand, metastatic inefficiency favours metachronous seeding patterns. That is, it predicts that the majority of cancer cells entering the liver are arrested and killed there, and that the development of liver metastases is a relatively slow process. Only small, nontumorigenic numbers of cancer cells therefore reach the lungs directly from the primary cancer; this direct seeding stops when the primary cancer is resected. It is therefore expected that only cancer cells released from the secondary liver metastases will successfully seed the lungs and that the majority of these will be arrested and killed there. Thus, arterial metastases are not expected to be seeded directly from liver metastases, but seeding is predicted from cancer cells released from tertiary lung metastases.

Evidence in favor of metachronous seeding comes from the analysis of autopsy reports, where groups were identified with liver metastases and none elsewhere; with liver and lung metastases and none elsewhere, and liver, lung, and arterial metastases.

Conversely, lung metastases seldom occurred in the absence of liver metastases, and arterial metastases seldom occurred in the absence of lung metastases. Recognition of this sequential pattern of haematogenous metastasis could advantageously be incorporated in staging systems.

Metachronous seeding can be accounted for in terms of anatomy and general metastatic inefficiency. However, specificity with respect to arterial metastatic patterns requires cell­microenvironmental interactions in the postdelivery phase of metastasis. As predicted by the "seed and soil" hypothesis of Paget in 1889, these interactions can either promote or inhibit metastatic development.

Analysis of human metastatic patterns has not been overly successful in the past, because of the difficulty in disentangling cancer cell delivery from the subsequent interactions at the target site. A method of discriminating between the delivery and postdelivery events has now been described: In essence, cancer cell delivery in the case of arterial metastases is considered to be proportional to target organ blood flow; this assumption is based on actual measurement made on laboratory animals. Values of human organ blood flow are obtained from recent measurements reported in the physiologic literature, and the incidence of arterial metastases in these sites is obtained from large autopsy series on patients dying with metastatic cancer. The ratio of blood flow (ml/min) to incidence (%) is termed the Metastatic Efficiency Index (MEI), which falls into three groups. Most sites are within the range of 0.01 to 0.09; values higher than 0.09 indicate postdelivery interactions favourable to metastasis development, whereas values of less than 0.01 indicate unfavourable interactions.

The brain as a whole falls into the middle range for most primary cancers, but into the "unfavourable" range «0.01) for osteosarcoma and ovarian, gastric, and bladder carcinomas. Unfortunately, it was not possible to match the incidence of metastases in different regions of the brain with differential blood flow on the bases of presently available data. These values for the whole brain are in contrast to the generally unfavourable range for skeletal muscle, and the highly favourable range for the adrenals. The posterior choroid of the eye is by far the most favourable site for metastasis development per unit of cancer cells delivered, from each of three types of primary cancers (breast 8.5 percent; colon, 4.2 percent; bronchus, 6.7 percent) although the actual incidence of intraocular metastasis, which partially reflects cancer cell delivery, is low. It is hoped that this type of numerical documentation will lead to studies of specific site-associated mechanisms of favourable and unfavourable interactions.

In vitro experiments, in which preferential adhesion of cancer cells to tissue sections has been reported, reflect neither differential arrest in the microvasculature under hemodynamic conditions, nor the differential growth of arrested/adherent cancer emboli. In vivo experiments have also been reported, in which cancer cells growing in colonies at different anatomic sites following intravenous injection, are "selected" by repetitive injections and harvesting procedures, for preferential growth in different sites following injection. Any interpretation of experiments of this type must take into account site-associated changes occurring in cancer cells after delivery, possibly indicated through interactions with the extracellular matrix. In addition, autopsy data fail to reveal preferential metastasis to one of paired organs from primary cancers in the other.

Molecular Biology of Metastasis: A Brief Overview

Some of the major recent advances in oncology have generally been in the area of molecular biology. and have focused on the role of oncogene and suppressor gene products in the poorly restricted growth of cancer cells. The proto-oncogenes encode proteins which transduce extracellular signals from the cell membrane to the nucleus which stimulate cell proliferation. Thus, mutations activating the oncogenic potential of cell proto-oncogenes can lead to loss of control of proliferation seen in normal cells. Mutations of this type, and those inactivating genes controlling growth suppression account for the development of cancer. although many of the detailed mechanisms presently require clarification. It is therefore not surprising that a great deal of recent research in metastasis has been directed at determining the molecular biology of metastasis.

A good example of the potential value of such research is provided by carcinoma of the breast, in patients without lymph node involvement. Approximately 15 percent of these patients subsequently develop metastases that warrant treatment by systemic chemotherapy. However, this 15 percent patient subpopulation cannot be identified on the basis of routine histologic examination, and the question arises whether all patients in this apparent NoMo category should be subjected to treatment. in order to "trap" the 15 percent minority. The problem could be resolved if probes were available to predict the biologic behaviour of individual tumors, over and above the group statistical evaluations obtained from standard histologic examination. A number of promising leads are currently under investigation, particularly in relation to carcinomas of the breast and colon.

From a clinical viewpoint, the salient features of metastasis concern the growth of primary cancers initially, and the subsequent growth of surviving cancer emboli into metastases. The potential for growth can be assessed by a number of histologic and immunohistologic procedures including mitotic index, BUdR­incorporation, Ki-67, and proliferating cell nuclear antigen (PCNA) expression. Proliferation potential can also be assessed with molecular biologic probes capable of detecting oncogene (e.g., C-erb-B2) and suppressor gene (e.g., NM23 and RB) products; expression, loss of expression, and mutations in these' gene products have been associated with metastatic status. However, at present there is no universal indicator for metastasis prediction that is applicable to all types of cancers, or even for breast and colonic cancers. The complexity of the metastatic process virtually precludes the existence of a universal metastatic gene, and from a mechanistic viewpoint it is important to discriminate between causal relationships and associations between up- or downregulation of gene products and metastasis. An example of multifunctional gene products has been hypothesized in connection with invasion, which is regarded as due to an imbalance between the activation of two sets of genes, an invasion promoter and an invasion suppressor such as TIMP. A cell adhesion molecule (E-cadherin, L-CAM, Uvomorulin) has been implicated as an invasion suppressor gene product.

Foulds' concept of tumor progression, originally described at the level of individual cells, involves irreversible steps leading from premalignant states to cancer. Confusion has been introduced into terminology by the clinical aphorism that "cancer goes from bad to worse," which is a reflection of the progressive deterioration in the patient's condition as the disease progresses, over time, as distinct from specific changes in cancer cells themselves.

Credit is due to Fidler for suggesting that subpopulations of cancer cells evolve that express a so-called metastatic phenotype, so that metastasis would be a nonrandom, selective process. In contrast, Weiss noted that even among cell lines that were cloned on the basis of metastasis-related properties the vast majority were destroyed during or after delivery, and that at the cancer cell level, metastasis is essentially a random process. Weiss favours the concept of a "transient metastatic compartment," in which at anyone time, the whole heterogeneous population of cancer cells within a tumor each possess different metastatic potential depending on metabolic and cycle status, host interactions, and topography. In other words, virtually all of the cancer cells in a tumor are potentially metastatic, but the probability of each cancer cell actually generating a metastasis varies from time to time, and is very low.

From a practical viewpoint, regardless of underlying random or nonrandom elements, the important conclusion is that at any time, some cancer cells in a surgical specimen of a potentially metastasizing tumor may express specific metastasis-related properties that, if identifiable and quantifiable, may have predictive prognostic value. At present, it seems likely that attempts to assess and predict the biologic behaviour of cancer will not depend on the use of a single metastasis-specific probe, but may well depend on the use of panels of probes, markers, and standard histologic assessments, not only of the cancer cells, but also of tumor/host interactions in, adjacent to, and distant from the tumor itself. The information obtained must be useful to the individual patient as distinct from cohorts of patients.


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