Lymphatic or Hematogenous Dissemination: How Does a Metastatic Tumor Cell Decide?
Abstract
The formation of distant metastases is the deadliest phase of cancer progression. Although numerous studies have identified genes and mechanisms that affect metastasis after tumors have reached secondary sites, our knowledge about how cancer cells initially gain access to systemic circulation is limited. Since tumors can enter the blood directly by intravasating into venous capillaries or indirectly via lymphatics, it is important to evaluate the relative contributions of both pathways as routes of egress from the primary site. Insights into tumor and stromal factors governing the intravasation process may help explain why certain tumors exhibit “preferred” pathways for metastatic dissemination, both clinically and in experimental animal models.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1459485/
Lymphatic or Hematogenous Dissemination: How Does a Metastatic Tumor Cell Decide?
Re: Lymphatic or Hematogenous Dissemination: How Does a Metastatic Tumor Cell Decide?
WHICH TUMORS METASTASIZE?
What makes a tumor cell metastatic? Certainly, proliferative ability at a distant site is essential for metastasis (Paget’s “seed and soil” hypothesis), and difficulties in establishing secondary growth might explain why fewer than 0.01% of circulating tumor cells actually form metastases.1–3 However, exactly what enables a cancer cell to complete the metastatic process is not entirely clear. While recent gene expression studies have suggested that distant metastases resemble their primary tumors of origin,4,5 other studies have indicated that the expression of specific genes is altered in metastatic cells.6–8 A model combining both these observations has speculated that cells derived from metastases and from their corresponding primary tumors share an overall gene expression signature that confers the ability to complete some, but not all, of the steps required for metastasis.7,9 On top of this, the altered expression of a limited number of additional genes may render a sub-population of cells fully competent for metastasis, without changing its overall similarity with the primary tumor.
Although metastasis is widely regarded as an inefficient process, most cancer patients die from metastases rather than from their primary tumors. Metastatic inefficiency is likely overcome by the sheer number of tumor cells that enter the systemic circulation daily, estimated in one study to be up to ~4 × 106 tumor cells released per gram of primary tumor.10 Consequently, it is important that we gain a detailed understanding of how tumors complete the earliest steps of metastasis, including intravasation into vasculature.
In order to metastasize, cancer cells must first detach from the primary tumor and invade blood vessels or lymphatics. This may be a passive process where cells are simply sloughed off from the primary tumor or an active one involving directed migration.11,12 Almost certainly, a tumor’s cell of origin and its accompanying differentiation program will affect its metastatic proclivity.13 Cells from connective tissue tumors such as fibrosarcomas and gliomas tend to migrate individually, for instance, whereas those from melanomas and carcinomas often migrate collectively.14 In addition, highly differentiated epithelial tumors may initially display collective migration, only to de-differentiate and exhibit single cell invasion, a process termed epithelial-to-mesenchymal-transition (EMT).15 Indeed, genes that promote EMT—including Twist;8 Slug and Snail transcription factors;16 and components of the TGF-β signaling pathway17,18—have all been reported to enhance the earliest stages of metastasis. E-cadherin, which is often lost during EMT, is thought to suppress cell migration and tumor progression.19 Finally, stromal cells such as fibroblasts and macrophages have also been reported to affect metastasis by contributing growth factors (e.g., EGF, FGF-1), matrix metalloproteinases and chemotactic/pro-migratory factors (e.g., SF/HGF, chemokines
This folks is why its important to have the primary removed if at all possible.
What makes a tumor cell metastatic? Certainly, proliferative ability at a distant site is essential for metastasis (Paget’s “seed and soil” hypothesis), and difficulties in establishing secondary growth might explain why fewer than 0.01% of circulating tumor cells actually form metastases.1–3 However, exactly what enables a cancer cell to complete the metastatic process is not entirely clear. While recent gene expression studies have suggested that distant metastases resemble their primary tumors of origin,4,5 other studies have indicated that the expression of specific genes is altered in metastatic cells.6–8 A model combining both these observations has speculated that cells derived from metastases and from their corresponding primary tumors share an overall gene expression signature that confers the ability to complete some, but not all, of the steps required for metastasis.7,9 On top of this, the altered expression of a limited number of additional genes may render a sub-population of cells fully competent for metastasis, without changing its overall similarity with the primary tumor.
Although metastasis is widely regarded as an inefficient process, most cancer patients die from metastases rather than from their primary tumors. Metastatic inefficiency is likely overcome by the sheer number of tumor cells that enter the systemic circulation daily, estimated in one study to be up to ~4 × 106 tumor cells released per gram of primary tumor.10 Consequently, it is important that we gain a detailed understanding of how tumors complete the earliest steps of metastasis, including intravasation into vasculature.
In order to metastasize, cancer cells must first detach from the primary tumor and invade blood vessels or lymphatics. This may be a passive process where cells are simply sloughed off from the primary tumor or an active one involving directed migration.11,12 Almost certainly, a tumor’s cell of origin and its accompanying differentiation program will affect its metastatic proclivity.13 Cells from connective tissue tumors such as fibrosarcomas and gliomas tend to migrate individually, for instance, whereas those from melanomas and carcinomas often migrate collectively.14 In addition, highly differentiated epithelial tumors may initially display collective migration, only to de-differentiate and exhibit single cell invasion, a process termed epithelial-to-mesenchymal-transition (EMT).15 Indeed, genes that promote EMT—including Twist;8 Slug and Snail transcription factors;16 and components of the TGF-β signaling pathway17,18—have all been reported to enhance the earliest stages of metastasis. E-cadherin, which is often lost during EMT, is thought to suppress cell migration and tumor progression.19 Finally, stromal cells such as fibroblasts and macrophages have also been reported to affect metastasis by contributing growth factors (e.g., EGF, FGF-1), matrix metalloproteinases and chemotactic/pro-migratory factors (e.g., SF/HGF, chemokines
This folks is why its important to have the primary removed if at all possible.
Debbie
Re: Lymphatic or Hematogenous Dissemination: How Does a Metastatic Tumor Cell Decide?
BLOOD VESSEL OR LYMPHATIC DISSEMINATION?
Once a migratory cell(s) has detached from the primary tumor, it may intravasate into blood vessels or lymphatics. Either route of dissemination can lead to venous circulation, as lymphatics drain into blood, most commonly through the left lymphatic duct (thoracic duct) or the right lymphatic duct, and then subsequently into the subclavian veins. Along the way, lymphatic fluid is filtered by lymph nodes.
In the absence of overt metastases, hematogenous dissemination of tumors is assayed by detecting cancer cells in the peripheral blood of patients or from bone marrow aspirates.20 The presence of circulating tumor cells and micrometastases can be determined by RT-PCR or immunohistochemistry (IHC), particularly for cytokeratins in the case of epithelial tumors. Lymphatic spread is also assayed by IHC and/or RT-PCR following surgical removal of regional lymph nodes. Tumors almost invariably invade lymph nodes in sequence, starting with the nearest (sentinel or draining) node, followed by increasingly distal ones.21 If the draining lymph node is uninvaded, other lymph nodes are also likely free of metastases.22
Metastatic bias is illustrated by the fact that carcinomas and melanomas tend to develop lymph node metastases more frequently than sarcomas,14 although it is unclear whether this disparity is due to differences in intravasation and/or growth. Lymph nodes are often the first site of metastasis in a variety of cancers, and are critical for tumor staging and prognosis.22 In prostate cancer, for instance, 75% of patients bearing lymph node metastases at the time of diagnosis will possess bone metastases within 5 years, regardless of treatment.23 The presence of tumor cells in the bone-marrow is also predictive of distant metastases in a variety of tumors, particularly carcinomas.20 On the other hand, the prognostic value of circulating tumor cells in the blood is debated, as current techniques for detection suffer from problems such as low sensitivity and high rates of false positives.24,25 However, recent studies using an automated platform for detecting tumor cells in the blood, called CellSearch, have reported significant correlations between the presence of circulating tumor cells and poor clinical outcome for breast cancer patients.26
The decision to intravasate into either blood or lymphatic vessels may rest largely on physical restrictions imposed on invasive tumors, although active mechanisms for attracting cells to specific types of vasculature have also recently been proposed (see below). Lymphatic capillaries lack the tight interendothelial junctions typically seen in blood vessels, as well as the surrounding layers of pericytes/smooth muscle cells and basement membranes.27 This inevitably renders lymphatics “leaky” relative to blood vessels, thus lowering the barriers for tumor intravasation. In addition, tumor cell survival may benefit from the passive, low-shear system of fluid transport characteristic of lymphatics.
Accessibility of blood and lymphatic vasculature may also influence the pathway taken for metastasis. Induction of angiogenesis, the growth of blood vessels, has been shown to be necessary for tumors growing beyond 0.4 mm in diameter.28,29 Lymphangiogenesis, the growth of lymphatic vessels, has been inhibited by us30 and others31–37 in experimental mouse cancer models without affecting primary tumor growth. Because blood and lymphatic vessels share a common embryonic origin, and respond to many similar growth factors—VEGF-A, VEGF-C, VEGF-D, FGF2, PDGF-B, HGF and others38—tumors might be expected to induce lymphangiogenesis concomitant with angiogenesis. But for reasons unclear, this is often not the case. While proliferating intratumoral lymphatics have been detected in human melanomas,39 as well as in head and neck squamous cell carcinomas,40 evidence for lymphangiogenesis in other cancers has been less well documented. The presence of anti-lymphangiogenic factors may be one reason why proliferating intratumoral lymphatics are not more commonly found in human clinical tumors,41 though the identity of these proposed factors is currently unknown.
Maybe Olga and or Bonni could clear this up for me.
Its my understanding that ASPS is disseminated mainily through the blood?
Once a migratory cell(s) has detached from the primary tumor, it may intravasate into blood vessels or lymphatics. Either route of dissemination can lead to venous circulation, as lymphatics drain into blood, most commonly through the left lymphatic duct (thoracic duct) or the right lymphatic duct, and then subsequently into the subclavian veins. Along the way, lymphatic fluid is filtered by lymph nodes.
In the absence of overt metastases, hematogenous dissemination of tumors is assayed by detecting cancer cells in the peripheral blood of patients or from bone marrow aspirates.20 The presence of circulating tumor cells and micrometastases can be determined by RT-PCR or immunohistochemistry (IHC), particularly for cytokeratins in the case of epithelial tumors. Lymphatic spread is also assayed by IHC and/or RT-PCR following surgical removal of regional lymph nodes. Tumors almost invariably invade lymph nodes in sequence, starting with the nearest (sentinel or draining) node, followed by increasingly distal ones.21 If the draining lymph node is uninvaded, other lymph nodes are also likely free of metastases.22
Metastatic bias is illustrated by the fact that carcinomas and melanomas tend to develop lymph node metastases more frequently than sarcomas,14 although it is unclear whether this disparity is due to differences in intravasation and/or growth. Lymph nodes are often the first site of metastasis in a variety of cancers, and are critical for tumor staging and prognosis.22 In prostate cancer, for instance, 75% of patients bearing lymph node metastases at the time of diagnosis will possess bone metastases within 5 years, regardless of treatment.23 The presence of tumor cells in the bone-marrow is also predictive of distant metastases in a variety of tumors, particularly carcinomas.20 On the other hand, the prognostic value of circulating tumor cells in the blood is debated, as current techniques for detection suffer from problems such as low sensitivity and high rates of false positives.24,25 However, recent studies using an automated platform for detecting tumor cells in the blood, called CellSearch, have reported significant correlations between the presence of circulating tumor cells and poor clinical outcome for breast cancer patients.26
The decision to intravasate into either blood or lymphatic vessels may rest largely on physical restrictions imposed on invasive tumors, although active mechanisms for attracting cells to specific types of vasculature have also recently been proposed (see below). Lymphatic capillaries lack the tight interendothelial junctions typically seen in blood vessels, as well as the surrounding layers of pericytes/smooth muscle cells and basement membranes.27 This inevitably renders lymphatics “leaky” relative to blood vessels, thus lowering the barriers for tumor intravasation. In addition, tumor cell survival may benefit from the passive, low-shear system of fluid transport characteristic of lymphatics.
Accessibility of blood and lymphatic vasculature may also influence the pathway taken for metastasis. Induction of angiogenesis, the growth of blood vessels, has been shown to be necessary for tumors growing beyond 0.4 mm in diameter.28,29 Lymphangiogenesis, the growth of lymphatic vessels, has been inhibited by us30 and others31–37 in experimental mouse cancer models without affecting primary tumor growth. Because blood and lymphatic vessels share a common embryonic origin, and respond to many similar growth factors—VEGF-A, VEGF-C, VEGF-D, FGF2, PDGF-B, HGF and others38—tumors might be expected to induce lymphangiogenesis concomitant with angiogenesis. But for reasons unclear, this is often not the case. While proliferating intratumoral lymphatics have been detected in human melanomas,39 as well as in head and neck squamous cell carcinomas,40 evidence for lymphangiogenesis in other cancers has been less well documented. The presence of anti-lymphangiogenic factors may be one reason why proliferating intratumoral lymphatics are not more commonly found in human clinical tumors,41 though the identity of these proposed factors is currently unknown.
Maybe Olga and or Bonni could clear this up for me.
Its my understanding that ASPS is disseminated mainily through the blood?
Debbie
Re: Lymphatic or Hematogenous Dissemination: How Does a Metastatic Tumor Cell Decide?
Olga states-
yes Debbie, based on where the metastases are found it is reasonable to assume that ASPS metastasizes trough the blood.
Debbie