Colorectal cancer is the third most common cancer in both men and women. The 5 year survival rate for this malignancy drops to 8% once the cancer has spread hematogenously to distant organs such as the liver or the lung. An increased understanding of the molecular basis of colon cancer metastasis is needed in order to devise novel therapies for prevention of late-stage disease. The critical first step in hematogenous metastasis of target organs is the """"""""tethering and rolling"""""""" attachment of circulating cancer cells onto vascular endothelium. Among the principal effectors of tethering and rolling interactions of cells under shear flow conditions are E-selectin/E-selectin ligands and the CD44/hyaluronic acid (HA) axis. While HA is the principal ligand for CD44, studies from our laboratory have revealed that specialized glycoforms of CD44 (known as HCELL) bind E-selectin with high affinity. We have recently found that CD44 on human colon cancer cells express the HCELL glycoform and binds both E-selectin and HA. Importantly, expression of CD44 variants and tumor cell binding to E-selectin have each been correlated with poor prognosis in colon cancer. The studies proposed herein seek to elucidate the relationship between HCELL/CD44 binding to its ligands E-selectin and HA, and the role these adhesive pathways play in the promotion of the metastatic cascade, from the initial tethering/rolling of tumor cells on endothelium through transmigration and tissue infiltration. With respect to this Program Announcement, we seek to define how the cancer microenvironment affects expression and function of CD44 (including glycosylations rendering E-selectin binding determinant(s)), a molecule expected to promote metastasis of colon cancer """"""""stem"""""""" cells.
The Specific Aims of this proposal are: (1) To analyze the expression level, surface distribution, and function of CD44 on colon carcinoma cells;(2) To determine whether microenvironmental factors can influence expression and distribution of isoforms/glycoforms of CD44 on colon carcinoma cells;and (3) To analyze the capacity of colon carcinoma cells to transmigrate and seed tissue sites by manipulating tumor cell CD44 expression/function and carbohydrate modifications. It is anticipated that results of the studies proposed herein will lead to a greater understanding of the role of CD44 as a molecular effector of colon cancer cell-endothelial interactions under hydrodynamic shear conditions. This information is fundamental to devising new therapeutic strategies to prevent colon cancer dissemination, and thus has profound implications for prevention of late-stage disease. Lay summary: The underlying molecular basis of colon cancer metastasis is poorly understood. The proposed studies will focus on CD44, a molecule that is associated with poor prognosis and disease progression. It is anticipated that information gathered from these studies will form the basis for development of therapeutics targeting CD44 in colon cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Microenvironment Study Section (TME)
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Howcroft, Thomas K
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Brigham and Women's Hospital
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Sackstein, Robert (2016) Fulfilling Koch's postulates in glycoscience: HCELL, GPS and translational glycobiology. Glycobiology 26:560-70
Sackstein, Robert (2012) Engineering cellular trafficking via glycosyltransferase-programmed stereosubstitution. Ann N Y Acad Sci 1253:193-200
Sackstein, Robert (2012) Glycoengineering of HCELL, the human bone marrow homing receptor: sweetly programming cell migration. Ann Biomed Eng 40:766-76
Thankamony, Sai P; Sackstein, Robert (2011) Enforced hematopoietic cell E- and L-selectin ligand (HCELL) expression primes transendothelial migration of human mesenchymal stem cells. Proc Natl Acad Sci U S A 108:2258-63
Jacobs, Pieter P; Sackstein, Robert (2011) CD44 and HCELL: preventing hematogenous metastasis at step 1. FEBS Lett 585:3148-58
Sackstein, Robert (2011) The biology of CD44 and HCELL in hematopoiesis: the 'step 2-bypass pathway' and other emerging perspectives. Curr Opin Hematol 18:239-48
Sackstein, Robert (2010) Directing stem cell trafficking via GPS. Methods Enzymol 479:93-105
Nigro, Julie; Wang, Aimin; Mukhopadhyay, Durba et al. (2009) Regulation of heparan sulfate and chondroitin sulfate glycosaminoglycan biosynthesis by 4-fluoro-glucosamine in murine airway smooth muscle cells. J Biol Chem 284:16832-9
Lee, Jack Y; Buzney, Catherine D; Poznansky, Mark C et al. (2009) Dynamic alterations in chemokine gradients induce transendothelial shuttling of human T cells under physiologic shear conditions. J Leukoc Biol 86:1285-94
Sackstein, Robert (2009) Glycosyltransferase-programmed stereosubstitution (GPS) to create HCELL: engineering a roadmap for cell migration. Immunol Rev 230:51-74

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