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Daniel Ramos D.D.S., Ph.D.

Integrin regulation of the invasion of tumor cells

Daniel Ramos D.D.S., Ph.D.

Oral Squamous cell Carcinoma Project
Squamous cell carcinoma (SCC) represents approximately 96% of all oral cancers. The 5 year survival rate for this disease has not improved in over 60 years and remains at 50%. During oral cancer progression, the cells lose their polarity and become undifferentiated through the process of Epithelial to Mesenchymal Transition (EMT). It is at this time when αvβ6 integrin is first expressed. The β6 integrin is upregulated in several epithelial malignancies including oral cancer and is associated with increased EMT. avβ6 can bind fibronectin and the latency associated peptide-1 (LAP) of TGFβ1. Binding of avβ6 to LAP activates TGFβ1. The overexpression of avβ6 on tumors, particularly at the tumor-stromal interface, may reflect a unique mechanism for local activation of TGFβ1. Our recent work has shown that the mesenchymal properties of the tumor cells associated with the invasive oral SCC cells is regulated by the cytoplasmic tail of the β6 and the removal of the tail redifferentiates the cells into a more epithelial phenotype which is characterized by increased expression of E-cadherin and keratin.


Melanoma cell project
Mucocutaneous melanoma has an extremely poor prognosis due its highly aggressive behavior. The five-year survival rate is less than 10%. Our previous studies in melanoma demonstrate that upregulation of the αvβ3 integrin is required to maintain the invasive phenotype. Invasion requires a continued extension and retraction of the cell membrane that is mediated by the actin cytoskeleton. Cofilin, a 21kD protein, is responsible for both polymerization and depolymerization of actin. We are working on defining the mechanism underlying cofilin function. Our preliminary results indicate that αvβ3 integrin promotes invasion by suppressing the default RhoA/ROCK/LIMK1 pathway.
 

Selected publications:

1.Siu A, Lee C, Pham E, Ramos DM. Revisiting Epithelial-to-mesenchymal Transition through Adenoid Cystic Carcinoma. Anticancer Res. 2012 Sep; 32(9):3683-8.

2.Siu A, Lee C, Dang D, Lee C, Ramos DM. Stem cell markers as predictors of oral cancer invasion. Anticancer Res. 2012 Apr; 32(4):1163-6.

3.Ramos D, Ades C. Two-Item Sentence Comprehension by a Dog (Canis familiaris). PLoS One. 2012; 7(2):e29689.

4.Ramos DM, Dang D. EMMPRIN expression in oral SCC is regulated by FYN kinase. Anticancer Res. 2011 Apr; 31(4):1205-9.

5.Lewin B, Siu A, Baker C, Dang D, Schnitt R, Eisapooran P, Ramos DM. Expression of Fyn kinase modulates EMT in oral cancer cells. Anticancer Res. 2010 Jul; 30(7):2591-6.

6.Dang D, Sadler S, Ramos DM. Modulation of EGFR by oral squamous cell carcinoma cell lines. J Calif Dent Assoc. 2009 Dec; 37(12):869-74.

7.Daniel AG, Lucas SR, Júnior AR, Monteiro PR, Ramos D, Pires CG, Sinhorini IL. Skin fragility syndrome in a cat with cholangiohepatitis and hepatic lipidosis. J Feline Med Surg. 2010 Feb; 12(2):151-5.

8.Ramos D, Mills DS. Human directed aggression in Brazilian domestic cats: owner reported prevalence, contexts and risk factors. J Feline Med Surg. 2009 Oct; 11(10):835-41.

9.Dang D, Ramos DM. Identification of {alpha}v{beta}6-positive stem cells in oral squamous cell carcinoma. Anticancer Res. 2009 Jun; 29(6):2043-9.

10.Ramos DM, Dang D, Sadler S. The role of the integrin alpha v beta6 in regulating the epithelial to mesenchymal transition in oral cancer. Anticancer Res. 2009 Jan; 29(1):125-30.

11.de Araujo CE, Ramos DM, Moyses RA, Durazzo MD, Cernea CR, Ferraz AR. Neck nerve trunks schwannomas: clinical features and postoperative neurologic outcome. Laryngoscope. 2008 Sep; 118(9):1579-82.

12.Dang D, Atakilit A, Ramos DM. EMMPRIN modulates migration and deposition of TN-C in oral squamous carcinoma. Anticancer Res. 2008 Jul-Aug; 28(4B):2049-54.

13.Essayem S, Kovacic-Milivojevic B, Baumbusch C, McDonagh S, Dolganov G, Howerton K, Larocque N, Mauro T, Ramirez A, Ramos DM, Fisher SJ, Jorcano JL, Beggs HE, Reichardt LF, Ilic D. Hair cycle and wound healing in mice with a keratinocyte-restricted deletion of FAK. Oncogene. 2006 Feb 16; 25(7):1081-9.

14.Dang D, Bamburg JR, Ramos DM. Alphavbeta3 integrin and cofilin modulate K1735 melanoma cell invasion. Exp Cell Res. 2006 Feb 15; 312(4):468-77.

15.Santos CP, Felipe YX, Braga PE, Ramos D, Lima RO, Segurado AC. Self-perception of body changes in persons living with HIV/AIDS: prevalence and associated factors. AIDS. 2005 Oct; 19 Suppl 4:S14-21.

16.Mogi S, Dang D, Van Waes C, Ellis D, Atakilit A, Ramos DM. The expression of integrin alpha(v)beta6 promotes the epithelial cell morphology and suppresses invasive behavior in transformed oral keratinocytes. Anticancer Res. 2005 Mar-Apr; 25(2A):751-5.

17.Westernoff TH, Jordan RC, Regezi JA, Ramos DM, Schmidt BL. Beta-6 Integrin, tenascin-C, and MMP-1 expression in salivary gland neoplasms. Oral Oncol. 2005 Feb; 41(2):170-4.

18.Yang Y, Dang D, Mogi S, Ramos DM. Tenascin-C deposition requires beta3 integrin and Src. Biochem Biophys Res Commun. 2004 Sep 24; 322(3):935-42.

19.Dang D, Yang Y, Li X, Atakilit A, Regezi J, Eisele D, Ellis D, Ramos DM. Matrix metalloproteinases and TGFbeta1 modulate oral tumor cell matrix. Biochem Biophys Res Commun. 2004 Apr 9; 316(3):937-42.

20.Yang Y, Dang D, Atakilit A, Schmidt B, Regezi J, Li X, Eisele D, Ellis D, Ramos DM. Specific alpha v integrin receptors modulate K1735 murine melanoma cell behavior. Biochem Biophys Res Commun. 2003 Sep 5; 308(4):814-9.