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Role of cancer microenvironment in metastasis: focus on colon cancer.

Gout S, Huot J - Cancer Microenviron (2008)

Bottom Line: In most cases, death will result from the formation of distal secondary sites called metastases.These mutations lead to unrestrained growth of the primary neoplasm and a propensity to detach and to progress through the subsequent steps of metastatic dissemination.This process depends tightly on the surrounding microenvironment.

View Article: PubMed Central - PubMed

Affiliation: Le Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, 9 rue McMahon, Quebec, Canada.

ABSTRACT
One person on three will receive a diagnostic of cancer during his life. About one third of them will die of the disease. In most cases, death will result from the formation of distal secondary sites called metastases. Several events that lead to cancer are under genetic control. In particular, cancer initiation is tightly associated with specific mutations that affect proto-oncogenes and tumour suppressor genes. These mutations lead to unrestrained growth of the primary neoplasm and a propensity to detach and to progress through the subsequent steps of metastatic dissemination. This process depends tightly on the surrounding microenvironment. In fact, several studies support the point that tumour development relies on a continuous cross-talk between cancer cells and their cellular and extracellular microenvironments. This signaling cross-talk is mediated by transmembrane receptors expressed on cancer cells and stromal cells. The aim of this manuscript is to review how the cancer microenvironment influences the journey of a metastatic cell taking liver invasion by colorectal cancer cells as a model.

No MeSH data available.


Related in: MedlinePlus

Extravasation of cancer cells is a multi-step process. The first step consists in the transient adhesion of cancer cells to the endothelium. It involves endothelial adhesion molecules such as E-selectin and P-selectin and their counter-receptors present on cancer cells. This step is associated with the rolling of the cancer cells on the endothelium (1). The second step consists in a firmer adhesion of cancer cells to endothelial cells (2). It is mediated through chemoattractants and cell adhesion molecules on the endothelium and integrins on the cancer cells. The third step is characterized by the extravasation of cancer cells through endothelial cell–cell junctions (3). EC Endothelial cells, TC tumour cell (adapted from [107])
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Fig5: Extravasation of cancer cells is a multi-step process. The first step consists in the transient adhesion of cancer cells to the endothelium. It involves endothelial adhesion molecules such as E-selectin and P-selectin and their counter-receptors present on cancer cells. This step is associated with the rolling of the cancer cells on the endothelium (1). The second step consists in a firmer adhesion of cancer cells to endothelial cells (2). It is mediated through chemoattractants and cell adhesion molecules on the endothelium and integrins on the cancer cells. The third step is characterized by the extravasation of cancer cells through endothelial cell–cell junctions (3). EC Endothelial cells, TC tumour cell (adapted from [107])

Mentions: The tumour microenvironment encountered by the invading cancer cells is a critical component of metastasis and should be permissive for the metastatic growth of incoming tumour cells [116]. Notably, the adhesive interactions between the cancer cells and the endothelial cells of the target organs are determining components of metastasis. These interactions determine the arrest of the circulatory cells in the capillaries and initiate the cascade of events that culminate in extravasation or diapedesis of the cancer cells in the colonized organs. The extravasation of circulating tumour cells in the host organ requires successive adhesive interactions between endothelial cells and their ligands or counter-receptors present on the cancer cells [117]. Typically, the colon cancer cell/endothelial cell interactions in the liver imply first a selectin-mediated initial attachment and rolling of the circulating cancer cells on the endothelium. The rolling cancer cells then become activated by locally released chemokines present at the surface of endothelial cells. This triggers the activation of integrins from the cancer cells allowing their firmer adhesion to members of the Ig-CAM family such as ICAM and VCAM, initiating the transendothelial migration and extravasation processes [118] (Fig. 5). Interestingly, the expression of endothelial adhesion receptors may be induced by the cancer cells via a paracrine pathway. This is supported by studies showing that culture medium supernatants of cancer cells can trigger the expression of E-selectin on endothelial cells suggesting that cancer cells may release cytokines such as TNF-α, IL-β or INF-γ that will directly activate endothelial cells to express E-selectin and by extension P-selectin, ICAM-2 or VCAM [119, 120]. On the other hand, other studies show that cancer cells may initiate the expression of endothelial adhesion molecules in more indirect ways. In particular, highly metastatic human colorectal and mouse lung carcinoma cells, on their entry into the hepatic microcirculation, initiate a rapid host inflammatory response by inducing TNF-α production in resident Kupffer cells. In turn, this event triggers the expression of E-selectin and VCAM by endothelial cells and enhances the binding and extravasation of the cancer cells across sinusoidal endothelial cells [121, 122]. Moreover, the kinetics of the host inflammatory response are tumour-type specific and rely on interactions with hepatic Kupffer cells, which supports the concept that the process is local and liver-specific. In this sense, the process of E-selectin- and other endothelial adhesion receptor-mediated metastasis appears to be local. In particular, increased hepatic local metastasis of B16F1 melanoma cells is observed following the administration of exogenous IL-1α, which induces the expression of vascular adhesion receptor expression, including E-selectin, VCAM-1 and ICAM-1 enabling cell arrest in terminal portal venules [123]. Moreover, syngenic colon adenocarcinoma C-26 cells trigger an endogenous inflammatory cascade upon entry into the liver. The cascade is absent in TNFR1-deficient mice, which is associated with reduced formation of liver metastases [124]. Overall, these findings indicate that, at least in the case of the formation of colorectal metastases in the liver, the process results from a local remodeling of the hepatic microenvironment that enables adhesion and extravasation of the cancer cells. In corollary, these results further suggest that hepatic remodeling involving E-selectin-mediated adhesion is an important component of the hepatic homing of colon cancer metastases.Fig. 5


Role of cancer microenvironment in metastasis: focus on colon cancer.

Gout S, Huot J - Cancer Microenviron (2008)

Extravasation of cancer cells is a multi-step process. The first step consists in the transient adhesion of cancer cells to the endothelium. It involves endothelial adhesion molecules such as E-selectin and P-selectin and their counter-receptors present on cancer cells. This step is associated with the rolling of the cancer cells on the endothelium (1). The second step consists in a firmer adhesion of cancer cells to endothelial cells (2). It is mediated through chemoattractants and cell adhesion molecules on the endothelium and integrins on the cancer cells. The third step is characterized by the extravasation of cancer cells through endothelial cell–cell junctions (3). EC Endothelial cells, TC tumour cell (adapted from [107])
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2654352&req=5

Fig5: Extravasation of cancer cells is a multi-step process. The first step consists in the transient adhesion of cancer cells to the endothelium. It involves endothelial adhesion molecules such as E-selectin and P-selectin and their counter-receptors present on cancer cells. This step is associated with the rolling of the cancer cells on the endothelium (1). The second step consists in a firmer adhesion of cancer cells to endothelial cells (2). It is mediated through chemoattractants and cell adhesion molecules on the endothelium and integrins on the cancer cells. The third step is characterized by the extravasation of cancer cells through endothelial cell–cell junctions (3). EC Endothelial cells, TC tumour cell (adapted from [107])
Mentions: The tumour microenvironment encountered by the invading cancer cells is a critical component of metastasis and should be permissive for the metastatic growth of incoming tumour cells [116]. Notably, the adhesive interactions between the cancer cells and the endothelial cells of the target organs are determining components of metastasis. These interactions determine the arrest of the circulatory cells in the capillaries and initiate the cascade of events that culminate in extravasation or diapedesis of the cancer cells in the colonized organs. The extravasation of circulating tumour cells in the host organ requires successive adhesive interactions between endothelial cells and their ligands or counter-receptors present on the cancer cells [117]. Typically, the colon cancer cell/endothelial cell interactions in the liver imply first a selectin-mediated initial attachment and rolling of the circulating cancer cells on the endothelium. The rolling cancer cells then become activated by locally released chemokines present at the surface of endothelial cells. This triggers the activation of integrins from the cancer cells allowing their firmer adhesion to members of the Ig-CAM family such as ICAM and VCAM, initiating the transendothelial migration and extravasation processes [118] (Fig. 5). Interestingly, the expression of endothelial adhesion receptors may be induced by the cancer cells via a paracrine pathway. This is supported by studies showing that culture medium supernatants of cancer cells can trigger the expression of E-selectin on endothelial cells suggesting that cancer cells may release cytokines such as TNF-α, IL-β or INF-γ that will directly activate endothelial cells to express E-selectin and by extension P-selectin, ICAM-2 or VCAM [119, 120]. On the other hand, other studies show that cancer cells may initiate the expression of endothelial adhesion molecules in more indirect ways. In particular, highly metastatic human colorectal and mouse lung carcinoma cells, on their entry into the hepatic microcirculation, initiate a rapid host inflammatory response by inducing TNF-α production in resident Kupffer cells. In turn, this event triggers the expression of E-selectin and VCAM by endothelial cells and enhances the binding and extravasation of the cancer cells across sinusoidal endothelial cells [121, 122]. Moreover, the kinetics of the host inflammatory response are tumour-type specific and rely on interactions with hepatic Kupffer cells, which supports the concept that the process is local and liver-specific. In this sense, the process of E-selectin- and other endothelial adhesion receptor-mediated metastasis appears to be local. In particular, increased hepatic local metastasis of B16F1 melanoma cells is observed following the administration of exogenous IL-1α, which induces the expression of vascular adhesion receptor expression, including E-selectin, VCAM-1 and ICAM-1 enabling cell arrest in terminal portal venules [123]. Moreover, syngenic colon adenocarcinoma C-26 cells trigger an endogenous inflammatory cascade upon entry into the liver. The cascade is absent in TNFR1-deficient mice, which is associated with reduced formation of liver metastases [124]. Overall, these findings indicate that, at least in the case of the formation of colorectal metastases in the liver, the process results from a local remodeling of the hepatic microenvironment that enables adhesion and extravasation of the cancer cells. In corollary, these results further suggest that hepatic remodeling involving E-selectin-mediated adhesion is an important component of the hepatic homing of colon cancer metastases.Fig. 5

Bottom Line: In most cases, death will result from the formation of distal secondary sites called metastases.These mutations lead to unrestrained growth of the primary neoplasm and a propensity to detach and to progress through the subsequent steps of metastatic dissemination.This process depends tightly on the surrounding microenvironment.

View Article: PubMed Central - PubMed

Affiliation: Le Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, 9 rue McMahon, Quebec, Canada.

ABSTRACT
One person on three will receive a diagnostic of cancer during his life. About one third of them will die of the disease. In most cases, death will result from the formation of distal secondary sites called metastases. Several events that lead to cancer are under genetic control. In particular, cancer initiation is tightly associated with specific mutations that affect proto-oncogenes and tumour suppressor genes. These mutations lead to unrestrained growth of the primary neoplasm and a propensity to detach and to progress through the subsequent steps of metastatic dissemination. This process depends tightly on the surrounding microenvironment. In fact, several studies support the point that tumour development relies on a continuous cross-talk between cancer cells and their cellular and extracellular microenvironments. This signaling cross-talk is mediated by transmembrane receptors expressed on cancer cells and stromal cells. The aim of this manuscript is to review how the cancer microenvironment influences the journey of a metastatic cell taking liver invasion by colorectal cancer cells as a model.

No MeSH data available.


Related in: MedlinePlus