Gene Expression Analysis of the Concomitant Existence of Lymphovascular and Perineural Invasion in Colorectal Cancer

Nadiah Abu, Nurul Syakima Ab Mutalib, Rahman Jamal


The invasion of cancer cells into the peritumoral, lymph node and perineural system could be detrimental on cancer patients. In colorectal cancer (CRC) patients, the presence of lymphovascular (LVI) and/or perineural (PNI) invasion could significantly influence the survival rates, treatment options and recurrence tendencies. To date, no study has analysed the concomitant existence of LVI and PNI in CRC, particularly in relation to the molecular profiles. Here, we reanalysed The Cancer Genome Atlas (TCGA) CRC datasets and focused on cases where the information regarding LVI and PNI are available (n=176). We performed differential gene expression, methylation and microRNA analysis by comparing between the groups having both or either LVI and PNI with the control group (LVI negative and PNI negative).  Although there were no significant difference in the methylation and miRNA profiles, we identified a number of differentially expressed genes (DEGs). The comparison between the LVI+PNI+ and LVI-PNI- groups revealed key DEGs including SFTA2, PHACTR3, CRABP2, ODZ3, GRP, HAP1 and HDAC9. Meanwhile, in the LVI-PNI+ vs LVI-PNI- group, some of the DEGs found were PTPRR, EFNA2, FGF20, IGFL4 and IGFBPL1. We believe that this study could be beneficial and add value to further understand the complex molecular profiles of CRC.

Full Text:



Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A, et al. Colorectal cancer statistics, 2017. CA: A Cancer Journal for Clinicians. 2017;67(3):177-93.

Rakha EA, Martin S, Lee AHS, Morgan D, Pharoah PDP, Hodi Z, et al. The prognostic significance of lymphovascular invasion in invasive breast carcinoma. Cancer. 2012;118(15):3670-80.

Mohammed ZM, McMillan DC, Edwards J, Mallon E, Doughty JC, Orange C, et al. The relationship between lymphovascular invasion and angiogenesis, hormone receptors, cell proliferation and survival in patients with primary operable invasive ductal breast cancer. BMC Clinical Pathology. 2013;13(1):31.

Nofech-Mozes S, Ackerman I, Ghorab Z, Ismiil N, Thomas G, Covens A, et al. Lymphovascular Invasion Is a Significant Predictor for Distant Recurrence in Patients With Early-Stage Endometrial Endometrioid Adenocarcinoma. American Journal of Clinical Pathology. 2008;129(6):912-7.

Luo HL, Chiang PH, Chen YT, Cheng YT. Lymphovascular invasion is a pathological feature related to aggressive cancer behavior and predicts early recurrence in prostate cancer. The Kaohsiung Journal of Medical Sciences. 2012;28(6):327-30.

Li P, He H-Q, Zhu C-M, Ling Y-H, Hu W-M, Zhang X-K, et al. The prognostic significance of lymphovascular invasion in patients with resectable gastric cancer: a large retrospective study from Southern China. BMC Cancer. 2015;15(1):370.

Aktekin A, Özkara S, Gürleyik G, Odabaşi M, Müftüoğlu T, Sağlam A. The Factors Effecting Lymphovascular Invasion in Adenocarcinoma of the Colon and Rectum. Indian Journal of Surgery. 2015;77(2):314-8.

Schopmann A, Tamandl D, Herberger B, Längle F, Birner P, Geleff S, et al. Comparison of Lymphangiogenesis between Primary Colorectal Cancer and Corresponding Liver Metastases. Anticancer Research. 2011;31(12):4605-11.

Xu B, Yu L, Zhao L-Z, Ma D-W. Prognostic factors in the patients with T2N0M0 colorectal cancer. World Journal of Surgical Oncology. 2016;14(1):76.

Chang S-C, Lin C-C, Wang H-S, Yang S-H, Jiang J-K, Lan Y-T, et al. Lymphovascular invasion determines the outcome of stage I colorectal cancer patients. Formosan Journal of Surgery. 2012;45(5):141-5.

Chivukula M, Brufsky A, Davidson NE. Small Beginnings: Do They Matter? The Importance of Lymphovascular Invasion in Early Breast Cancer. JNCI: Journal of the National Cancer Institute. 2009;101(10):698-9.

Lee AHS, Pinder SE, Macmillan RD, Mitchell M, Ellis IO, Elston CW, et al. Prognostic value of lymphovascular invasion in women with lymph node negative invasive breast carcinoma. European Journal of Cancer.42(3):357-62.

Pontius L, Youngwirth L, Thomas S, Scheri R, Roman S, Sosa JA. Lymphovascular invasion is associated with survival for papillary thyroid cancer. Endocrine-Related Cancer. 2016.

Song YJ, Shin SH, Cho JS, Park MH, Yoon JH, Jegal YJ. The Role of Lymphovascular Invasion as a Prognostic Factor in Patients with Lymph Node-Positive Operable Invasive Breast Cancer. Journal of Breast Cancer. 2011;14(3):198-203.

Liebig C, Ayala G, Wilks JA, Berger DH, Albo D. Perineural invasion in cancer. Cancer. 2009;115(15):3379-91.

Vural C, Bayrak B, Muezz, #305, noglu B, Yucesoy I. Perineural invasion is a valuable prognostic factor in advanced stage and/or Node (+) cervical cancer. Indian Journal of Pathology and Microbiology. 2017;60(1):27-32.

Prueitt RL, Yi M, Hudson RS, Wallace TA, Howe TM, Yfantis HG, et al. Expression of microRNAs and protein-coding genes associated with perineural invasion in prostate cancer. The Prostate. 2008;68(11):1152-64.

Zareba P, Flavin R, Isikbay M, Rider JR, Gerke TA, Finn S, et al. Perineural Invasion and Risk of Lethal Prostate Cancer. Cancer Epidemiology Biomarkers & Prevention. 2017;26(5):719.

Hirai I, Kimura W, Ozawa K, Kudo S, Suto K, Kuzu H, et al. Perineural Invasion in Pancreatic Cancer. Pancreas. 2002;24(1):15-25.

Liebig C, Ayala G, Wilks J, Verstovsek G, Liu H, Agarwal N, et al. Perineural Invasion Is an Independent Predictor of Outcome in Colorectal Cancer. Journal of Clinical Oncology. 2009;27(31):5131-7.

Poeschl EM, Pollheimer MJ, Kornprat P, Lindtner RA, Schlemmer A, Rehak P, et al. Perineural Invasion: Correlation With Aggressive Phenotype and Independent Prognostic Variable in Both Colon and Rectum Cancer. Journal of Clinical Oncology. 2010;28(21):e358-e60.

van Wyk HC, Going J, Horgan P, McMillan DC. The role of perineural invasion in predicting survival in patients with primary operable colorectal cancer: A systematic review. Critical Reviews in Oncology / Hematology.112:11-20.

Moo Jun Baek HWL, Tae Sung Ahn, Sung Woo Cho, Eung Jin Shin, Nae Kyung Park, Moon Soo Lee, Chang Ho Kim. Clinical Significance of Perineural Invasion in Colorectal Cancer Korean J Clin Oncol. 2012;8(1):30-6.

Kosmider S, Lipton L. Adjuvant therapies for colorectal cancer. World Journal of Gastroenterology : WJG. 2007;13(28):3799-805.

Dienstmann R, Salazar R, Tabernero J. Personalizing Colon Cancer Adjuvant Therapy: Selecting Optimal Treatments for Individual Patients. Journal of Clinical Oncology. 2015;33(16):1787-96.

Nikberg M, Chabok A, Letocha H, Kindler C, Glimelius B, Smedh K. Lymphovascular and perineural invasion in stage II rectal cancer: a report from the Swedish colorectal cancer registry. Acta Oncologica. 2016;55(12):1418-24.

Hwang J-E, Hong J-Y, Kim JE, Shim H-J, Bae W-K, Hwang E-C, et al. Prognostic significance of the concomitant existence of lymphovascular and perineural invasion in locally advanced gastric cancer patients who underwent curative gastrectomy and adjuvant chemotherapy. Japanese Journal of Clinical Oncology. 2015;45(6):541-6.

Rich JT, Neely JG, Paniello RC, Voelker CCJ, Nussenbaum B, Wang EW. A PRACTICAL GUIDE TO UNDERSTANDING KAPLAN-MEIER CURVES. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery. 2010;143(3):331-6.

Wang J, Duncan D, Shi Z, Zhang B. WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013. Nucleic Acids Research. 2013;41(Web Server issue):W77-W83.

Kanehisa M, Goto S. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Research. 2000;28(1):27-30.

Mittal RA, Hammel M, Schwarz J, Heschl KM, Bretschneider N, Flemmer AW, et al. SFTA2—A Novel Secretory Peptide Highly Expressed in the Lung—Is Modulated by Lipopolysaccharide but Not Hyperoxia. PLOS ONE. 2012;7(6):e40011.

Xiao J, Lu X, Chen X, Zou Y, Liu A, Li W, et al. Eight potential biomarkers for distinguishing between lung adenocarcinoma and squamous cell carcinoma. Oncotarget. 2017.

Itoh A, Uchiyama A, Taniguchi S, Sagara J. Phactr3/Scapinin, a Member of Protein Phosphatase 1 and Actin Regulator (Phactr) Family, Interacts with the Plasma Membrane via Basic and Hydrophobic Residues in the N-Terminus. PLOS ONE. 2014;9(11):e113289.

Sagara J, Arata T, Taniguchi S. Scapinin, the Protein Phosphatase 1 Binding Protein, Enhances Cell Spreading and Motility by Interacting with the Actin Cytoskeleton. PLOS ONE. 2009;4(1):e4247.

Bosch LJW, Oort FA, Neerincx M, Khalid-de Bakker CAJ, sive Droste JST, Melotte V, et al. DNA Methylation of Phosphatase and Actin Regulator 3 Detects Colorectal Cancer in Stool and Complements FIT. Cancer Prevention Research. 2012;5(3):464-72.

Vreeland AC, Levi L, Zhang W, Berry DC, Noy N. Cellular retinoic acid-binding protein 2 inhibits tumor growth by two distinct mechanisms. Journal of Biological Chemistry. 2014.

Yuan J, Tang Z, Yang S, Li K. CRABP2 Promotes Myoblast Differentiation and Is Modulated by the Transcription Factors MyoD and Sp1 in C2C12 Cells. PLoS ONE. 2013;8(1):e55479.

Xiao W, Hong H, Awadallah A, Yu S, Zhou L, Xin W. CRABP-II is a highly sensitive and specific diagnostic molecular marker for pancreatic ductal adenocarcinoma in distinguishing from benign pancreatic conditions. Human pathology. 2014;45(6):1177-83.

Yang Q, Wang R, Xiao W, Sun F, Yuan H, Pan Q. Cellular Retinoic Acid Binding Protein 2 Is Strikingly Downregulated in Human Esophageal Squamous Cell Carcinoma and Functions as a Tumor Suppressor. PLoS ONE. 2016;11(2):e0148381.

Favorskaya I, Kainov Y, Chemeris G, Komelkov A, Zborovskaya I, Tchevkina E. Expression and clinical significance of CRABP1 and CRABP2 in non-small cell lung cancer. Tumor Biology. 2014;35(10):10295-300.

Tucker RP, Chiquet-Ehrismann R. Teneurins: A conserved family of transmembrane proteins involved in intercellular signaling during development. Developmental Biology. 2006;290(2):237-45.

Tucker RP, Kenzelmann D, Trzebiatowska A, Chiquet-Ehrismann R. Teneurins: Transmembrane proteins with fundamental roles in development. The International Journal of Biochemistry & Cell Biology. 2007;39(2):292-7.

Aldahmesh MA, Mohammed JY, Al-Hazzaa S, Alkuraya FS. Homozygous null mutation in ODZ3 causes microphthalmia in humans. Genet Med. 2012;14(11):900-4.

Solyom S, Ewing AD, Rahrmann EP, Doucet TT, Nelson HH, Burns MB, et al. Extensive somatic L1 retrotransposition in colorectal tumors. Genome Research. 2012.

Saurin JC, Rouault JP, Abello J, Berger F, Remy L, Chayvialle JA. High gastrin releasing peptide receptor mRNA level is related to tumour dedifferentiation and lymphatic vessel invasion in human colon cancer. European Journal of Cancer. 1999;35(1):125-32.

Carroll RE, Matkowskyj KA, Chakrabarti S, McDonald TJ, Benya RV. Aberrant expression of gastrin-releasing peptide and its receptor by well-differentiated colon cancers in humans. American Journal of Physiology - Gastrointestinal and Liver Physiology. 1999;276(3):G655-G65.

Chao C, Ives K, Hellmich HL, Townsend CM, Hellmich MR. Gastrin-Releasing Peptide Receptor In Breast Cancer Mediates Cellular Migration And Interleukin-8 Expression. The Journal of surgical research. 2009;156(1):26-31.

Fang MZ, Liu C, Song Y, Yang G-Y, Nie Y, Liao J, et al. Over-expression of gastrin-releasing peptide in human esophageal squamous cell carcinomas. Carcinogenesis. 2004;25(6):865-71.

Matkowskyj KA, Keller K, Glover S, Kornberg L, Tran-Son-Tay R, Benya RV. Expression of GRP and Its Receptor in Well-differentiated Colon Cancer Cells Correlates with the Presence of Focal Adhesion Kinase Phosphorylated at Tyrosines 397 and 407. Journal of Histochemistry & Cytochemistry. 2003;51(8):1041-8.

Cornelio DB, Roesler R, Schwartsmann G. Gastrin-releasing peptide receptor as a molecular target in experimental anticancer therapy. Annals of Oncology. 2007;18(9):1457-66.

Heuser M, Schlott T, Schally AV, Kahler E, Schliephake R, Laabs SO, et al. Expression Of Gastrin Releasing Peptide Receptor In Renal Cell Carcinomas: A Potential Function For The Regulation Of Neoangiogenesis And Microvascular Perfusion. The Journal of Urology. 2005;173(6):2154-9.

Fleischmann A, Waser B, Reubi JC. High expression of gastrin-releasing peptide receptors in the vascular bed of urinary tract cancers: promising candidates for vascular targeting applications. Endocrine-Related Cancer. 2009;16(2):623-33.

Lapierre M, Linares A, Dalvai M, Duraffourd C, Bonnet S, Boulahtouf A, et al. Histone deacetylase 9 regulates breast cancer cell proliferation and the response to histone deacetylase inhibitors. Oncotarget. 2016;7(15):19693-708.

Rastogi B, Raut SK, Panda NK, Rattan V, Radotra BD, Khullar M. Overexpression of HDAC9 promotes oral squamous cell carcinoma growth, regulates cell cycle progression, and inhibits apoptosis. Molecular and Cellular Biochemistry. 2016;415(1):183-96.

Yuan Z, Peng L, Radhakrishnan R, Seto E. Histone Deacetylase 9 (HDAC9) Regulates the Functions of the ATDC (TRIM29) Protein. Journal of Biological Chemistry. 2010;285(50):39329-38.

Chou C-W, Wu M-S, Huang W-C, Chen C-C. HDAC Inhibition Decreases the Expression of EGFR in Colorectal Cancer Cells. PLOS ONE. 2011;6(3):e18087.

Van Den Maagdenberg AMJM, Bächner D, Schepens JTG, Peters W, Fransen JAM, Wieringa B, et al. The mouse Ptprr gene encodes two protein tyrosine phosphatases, PTP-SL and PTPBR7, that display distinct patterns of expression during neural development. European Journal of Neuroscience. 1999;11(11):3832-44.

Li X, Liu Z, Li W, Sun N, Xu Y, Xie Z, et al. PTPRR regulates ERK dephosphorylation in depression mice model. Journal of Affective Disorders. 2016;193:233-41.

Duś-Szachniewicz K, Woźniak M, Nelke K, Gamian E, Gerber H, Ziółkowski P. Protein tyrosine phosphatase receptor R and Z1 expression as independent prognostic indicators in oral squamous cell carcinoma. Head & Neck. 2015;37(12):1816-22.

Menigatti M, Cattaneo E, Sabates-Bellver J, Ilinsky VV, Went P, Buffoli F, et al. The protein tyrosine phosphatase receptor type R gene is an early and frequent target of silencing in human colorectal tumorigenesis. Molecular Cancer. 2009;8(1):124.

Astin JW, Batson J, Kadir S, Charlet J, Persad RA, Gillatt D, et al. Competition amongst Eph receptors regulates contact inhibition of locomotion and invasiveness in prostate cancer cells. Nat Cell Biol. 2010;12(12):1194-204.

Fukai J, Fujita K, Yamoto T, Sasaki T, Uematsu Y, Nakao N. Intracranial extension of adenoid cystic carcinoma: potential involvement of EphA2 expression and epithelial-mesenchymal transition in tumor metastasis: a case report. BMC Research Notes. 2014;7:131-.

Jeffers M, Shimkets R, Prayaga S, Boldog F, Yang M, Burgess C, et al. Identification of a Novel Human Fibroblast Growth Factor and Characterization of Its Role in Oncogenesis. Cancer Research. 2001;61(7):3131-8.

Smith P, Nicholson LJ, Syed N, Payne A, Hiller L, Garrone O, et al. Epigenetic Inactivation Implies Independent Functions for Insulin-like Growth Factor Binding Protein (IGFBP)-Related Protein 1 and the Related IGFBPL1 in Inhibiting Breast Cancer Phenotypes. Clinical Cancer Research. 2007;13(14):4061-8.

Gonda Y, Sakurai H, Hirata Y, Tabata H, Ajioka I, Nakajima K. Expression profiles of Insulin-like growth factor binding protein-like 1 in the developing mouse forebrain. Gene Expression Patterns. 2007;7(4):431-40.

Emtage P, Vatta P, Arterburn M, Muller MW, Park E, Boyle B, et al. IGFL: A secreted family with conserved cysteine residues and similarities to the IGF superfamily. Genomics. 2006;88(4):513-20.


  • There are currently no refbacks.
Asia-Pacific Journal of Molecular Medicine (APJMM),
C/o: Level 8, UKM Medical Molecular Biology Institute (UMBI), UKM Medical Centre,
Jalan Ya’acob Latiff, Bandar Tun Razak,
56000 Cheras, Kuala Lumpur, MALAYSIA
Tel: +6 03 9145 6321/9239
Fax: +6 03 9171 7185