Mechanical Entrapment Is Insufficient and Intercellular Adhesion Is Essential for Metastatic Cell Arrest in Distant Organs

Glinskii, Olga V.; Huxley, Virginia H.; Glinsky, Gennadi V.; Pienta, Kenneth J.; Raz, Avraham; Glinsky, Vladislav V.

doi:10.1593/neo.04646

Cited by 161 publications

(137 citation statements)

References 21 publications

Supporting

Mentioning

134

Contrasting

Unclassified

Order By: Relevance

“…Paget's "seed and soil" hypothesis posits that cancer cells can only survive and grow in appropriate environments; the reversible phenotypic plasticity of cancer cells during EMT and MErT is therefore one way in which cancer cells can adapt to the foreign soil of ectopic organ microenviron- ments. Expression of adhesion molecules has been shown to be necessary to complete the final steps of the metastatic cascade including intravasation and colonization [27]. Based on previous observations of increased E-cadherin expression in metastases compared to primary tumors, we expanded our analysis to include E-cadherin binding partner β-catenin, gap junction molecules Cx26 and Cx43 and mesenchymal markers FSP1 and vimentin to discern whether a full or partial MErT occurs (summarized in Table 1).…”

Section: Discussionmentioning

confidence: 99%

Partial Mesenchymal to Epithelial Reverting Transition in Breast and Prostate Cancer Metastases

Chao

Acquafondata

et al. 2011

Cancer Microenvironment

140

View full text Add to dashboard Cite

Epithelial to mesenchymal transition (EMT) is an oft-studied mechanism for the initiation of metastasis. We have recently shown that once cancer cells disseminate to a secondary organ, a mesenchymal to epithelial reverting transition (MErT) may occur, which we postulate is to enable metastatic colonization. Despite a wealth of in vitro and in vivo studies, evidence supportive of MErT in human specimens is rare and difficult to document because clinically detectable metastases are typically past the micrometastatic stage at which this transition is most likely evident. We obtained paired primary and metastatic tumors from breast and prostate cancer patients and evaluated expression of various epithelial and mesenchymal markers by immunohistochemistry. The metastases exhibited increased expression of membranous E-cadherin compared to primary tumors, consistent with EMT at the primary site and MErT at the metastatic site. However, the re-emergence of the epithelial phenotype was only partial or incomplete. Expression of epithelial markers connexins 26 and/or 43 was also increased on the majority of metastases, particularly those to the brain. Despite the upregulation of epithelial markers in metastases, expression of mesenchymal markers vimentin and FSP1 was mostly unchanged. We also examined prostate carcinoma metastases of varied sizes and found that while E-cadherin expression was increased compared to the primary lesion, the expression inversely correlated with size of the metastasis. This not only suggests that a second EMT may occur in the ectopic site for tumor growth or to seed further metastases, but also provides a basis for the failure to discern epithelial phenotypes in clinically examined macrometastases. In summary, we report increased expression of epithelial markers and persistence of mesenchymal markers consistent with a partial MErT that readily allows for a second EMT at the metastatic site. Our results suggest that cancer cells continue to display phenotypic plasticity beyond the EMT that initiates metastasis.

show abstract

Section: Discussionmentioning

confidence: 99%

Partial Mesenchymal to Epithelial Reverting Transition in Breast and Prostate Cancer Metastases

Chao

Acquafondata

et al. 2011

Cancer Microenvironment

140

View full text Add to dashboard Cite

show abstract

“…This has implications for therapeutic strategies, because exposure of galectins at the luminal site of tumor vessels makes them more easily accessible for drugs. It has already been shown that blocking endothelial galectins can inhibit tumor angiogenesis 10,15,31 and tumor metastasis 21,23,[32][33][34] both in vitro and in vivo. The observation that several galectins are presented extracellularly by activated endothelial cells could facilitate the development of novel therapeutic or diagnostic applications.…”

Section: Discussionmentioning

confidence: 99%

The Galectin Profile of the Endothelium

Thijssen

Hulsmans

Griffioen³

2008

The American Journal of Pathology

170

View full text Add to dashboard Cite

We previously identified overexpression of galectin-1 in activated tumor endothelium. Currently, the tumor vasculature is a target for therapeutic approaches. Little is known about galectin expression and regulation in the tumor vasculature. Here, we report the expression of galectin-1/-3/-8/-9 in the endothelium as determined by quantitative PCR, Western blot, flow cytometry, and immunohistochemistry. Galectin-2/-4/-12 were detectable at the mRNA level, albeit very low. Galectin-8 and -9 displayed alternative splicing. Immunohistochemistry of normal tissues revealed a broad but low expression of galectin-1 in the vasculature, whereas the expression levels and localization of the other galectins varied. Endothelial cell activation in vitro significantly increased the expression of galectin-1 (5.32 ؎ 1.97; P ‫؍‬ 0.04) and decreased the expression of both galectin-8 (0.59 ؎ 0.12; P < 0.04) and galectin-9 (0.32 ؎ 0.06; P < 0.002). Galectin-3 expression was unaltered. Although a portion of these proteins is expressed intracellularly, the membrane protein level of galectin-1/-8/-9 was significantly increased on cell activation in vitro, 6-fold (P ‫؍‬ Galectins are a family of proteins that share a binding affinity for ␤-galactoside-containing carbohydrates. Several members of this family are emerging as targets for cancer therapy. Apart from a direct role in cell transformation, their main contribution to tumor progression involves modification of the antitumor immune response and enhancement of the metastatic potential of tumor cells.1 There are several reports showing altered galectin expression profiles in tumor cells of different origin, [2][3][4] and compounds that interfere with galectin function in tumor cells are therefore considered for cancer therapy.An attractive site for therapeutic applications is the endothelium, ie, the monolayer of endothelial cells lining blood vessels. Endothelial cells in the tumor vasculature are easily accessible and less prone to become drug resistant, and disrupting the tumor endothelium results in massive death of tumor cells.5 Moreover, tumor endothelial cells express molecules that allow specific targeting independent of the tumor type eg, integrin ␣V␤3, CD44v3, and CD105.6 -9 Recently, we identified galectin-1 as a target molecule in the tumor endothelium. Activated tumor endothelial cells increase the expression of galectin-1, and ablation of its expression in vitro and in vivo results in impaired endothelial cell function and hampered tumor angiogenesis.10 Whether other galectins are also directly involved in endothelial cell biology and tumor angiogenesis is less well studied (for review, see Ref. 11). In the current study, we analyzed the expression of all known human galectins in the endothelium to get more insight in their possible function in endothelial cell biology. We show that multiple galectins and galectin isoforms are expressed by endothelial cells. Furthermore, the expression and distribution of endothelial galectins is altered on cell activation. These obser...

show abstract

“…Similar results of specific cell adhesions within the microvasculature of target organs were reported by others. 14,28 For example, using different experimental approaches and breast and prostate cancer cells, Glinskii and colleagues 29,30 demonstrated that mechanical entrapment is not sufficient for metastatic cell arrest in distant organs, whereas intercellular adhesion appears to be essential for this process. Using isolated, ventilated, and perfused rat and mouse lungs Al-Mehdi and colleagues 14 reported that metastatic HT1080 fibrosarcoma cells attached to the endothelia of pulmonary precapillary arterioles and capillaries that had diameters considerably larger than the tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Organ-Specific Metastatic Tumor Cell Adhesion and Extravasation of Colon Carcinoma Cells with Different Metastatic Potential

Schlüter

Gaßmann

Enns

et al. 2006

The American Journal of Pathology

121

112

View full text Add to dashboard Cite

Adhesive and invasive characteristics appear to be crucial for organ-specific metastasis formation. Using intravital microscopy we investigated the relation between the metastatic potential of colon carcinoma cells and their adhesive and invasive behavior during early steps of metastasis within microvasculatures of rat liver, lung, intestine, skin, muscle, spleen, and kidney in vivo. Colorectal carcinomas will affect ϳ6% of the population in the Western countries during their lifetime. These carcinomas are the third leading cause of cancer-related deaths among women and men and are the most important malignancies of the gut.1 Approximately 50% of the cancer patients die within 5 years because of cancerrelated problems, mostly attributable to metastatic lesions caused by the spread of cancers to near and distant sites. Even after potentially curative surgery, more than 30% of the patients with colorectal carcinomas subsequently develop metastases demonstrating that the spread from primary tumors to distant organs is usually the life-limiting aspect in colorectal carcinoma patients. 2Similar to other cancer entities, colorectal carcinomas often show organ preference of metastasis formation. The liver is the most common organ in which colorectal carcinomas establish distant metastases, and the liver is involved in more than 70% of patients with colorectal metastases. However, in 40 to 50% of these patients with liver metastases, other organs are also involved in metastatic colonization. The second most important organ for colorectal cancer metastasis is the lung, and 20 to 30% of all distant colorectal carcinoma metastases are found primarily in the lung. Isolated lung metastases with no evidence of other organ involvement are found in 5 to 10% of colorectal cancer patients. Other organs, such as the central nervous system, adrenal glands, spleen, skeleton, or skin together account for less than 10% of all colorectal metastases. 2,3The metastatic process consists of a number of sequential, interrelated steps that can all be rate limiting. 4,5 An important and early step during formation of distant metastasis appears to be the arrest of circulating tumor cells within the host organ.6,7 Approximately a century ago, two major hypotheses on the mechanisms of tumor cell arrest in metastatic host organs were proposed. Ewing 8 assumed that the random mechanical lodgment of Supported by the Innovative Medizinische Forschung Fund (University Hospital Mü nster) (Ha 1 2 01 01 to J.H.).K.S. and P.G. contributed equally to this study.

show abstract

Mechanical Entrapment Is Insufficient and Intercellular Adhesion Is Essential for Metastatic Cell Arrest in Distant Organs

Cited by 161 publications

References 21 publications

Partial Mesenchymal to Epithelial Reverting Transition in Breast and Prostate Cancer Metastases

Partial Mesenchymal to Epithelial Reverting Transition in Breast and Prostate Cancer Metastases

The Galectin Profile of the Endothelium

Organ-Specific Metastatic Tumor Cell Adhesion and Extravasation of Colon Carcinoma Cells with Different Metastatic Potential

Contact Info

Product

Resources

About