Abstract:

Oral squamous cell carcinoma is a multi-factorial disease and no single causative factor has been primarily held responsible. Its pathogenesis is a multistep process involving initiation, promotion and tumor progression. The tumor micro-environment, particularly the collagen characteristics, and mesenchymal cells like myofibroblasts are increasingly implicated. The present study aims to determine the myofibroblast distribution and stromal characteristics in different grades of oral squamous cell carcinoma. Total of 46 specimens of different grades of oral squamous cell carcinoma were selected from departmental archives and subjected to immunohistochemical evaluation of myofibroblasts using α-smooth muscle actin marker. Parallel sections were subjected to van gieson staining to determine the characteristics of the collagen of the tumor stroma. Statistical analysis was performed for comparison between the different grades of oral squamous cell carcinoma. 80% of squamous cell carcinoma specimens were positive for α-smooth muscle actin.  Poorly differentiated carcinoma specimens consistently demonstrated higher concentration of α-SMA positive myofibroblasts and a dense stroma. There was a positive correlation between myofibroblasts and the stromal density. The interesting feature was the higher concentration of myofibroblasts in the stroma away from the tumor islands the results indicate that the effect of the myofibroblasts on the tumor stroma may play a role in the fundamental cellular processes essential for tumor progression. It is well known that TGF-β dependent accumulation of collagen type 1 in tumor microenvironment is related to increased tumor invasiveness. Therefore, myofibroblasts may play a role in tumor growth and invasion.

References:

[1]. Abeloff, M. D., Armitage, J. O., Niederhuber, J. E., Kastan, M. B, McKenna, W. G., eds., 2008, Abeloff’s Clinical Oncology. 4th ed. Philadelphia, Pa: Elsevier Churchill Livingstone.

[2]. Wynder, E. L., Stellman, S. D., 1977, Comparative epidemiology of tobacco-related cancers. Cancer Res., 37, 4608-22.

[3]. De, Wever, O. and Mareel, M., 2003, Role of tissue stroma in cancer cell invasion. J. Pathol., 200, 429–44

[4]. Schiich, W., Lagac, R., Seemayer, T. A., 1982, Myofibroblastic stromal reaaction in retracted scirrhous carcinomas of the breast. Surg Gynecol and Obstet, 154,525-533.

[5]. Lagace, R., Grimaud, J. A., Schiirch, W., Seemayer, T. A., 1985, Stromal reaction in carcinomas of the breast and variations of collagenous matrix and structural glycoproteins. Virchows Arch [A], 408, 49-59

[6]. Bhawan, I., Bacchetta, C., Majno, G. A., 1979, Myofibroblastic tumor. Infantile digital fibroma (recurrent digital fibrous tumor of childhood). Am J PathoI, 94, 19-36

[7]. Tremblay, G., 1979, Stromal aspects of breast carcmoma. Exp Mol Pathol, 31, 248-260.

[8]. Lazard, D., Sastre, X., Frid, M. G., Glukhova, M. A., Thiery, J. P., and Koteliansky, V. E., 1993, Expression of smooth muscle-specific proteins in myoepithelium and stromal myofibroblasts of normal and malignant human breast tissue. Proc. Nati. Acad. Sci. USA, 90, 999-1003.

[9]. Kellermann, M. G., Sobral, L. M., da Silva, S. D., Zecchin, K. G., Graner, E., Lopes, M. A., Nishimoto, I., Kowalski, L. P., & Coletta, R. D. ,2007. Myofibroblasts in the stroma of oral squamous cell carcinoma are associated with poor prognosis. Histopathology, 51(6), 849–853. https://doi.org/10.1111/j.1365-2559.2007.02873.x

[10]. Amatangelo, M. D., Bassi, D. E., Klein-Szanto, A. J., & Cukierman, E. 2005, Stroma-derived three-dimensional matrices are necessary and sufficient to promote desmoplastic differentiation of normal fibroblasts. The American journal of pathology, 167(2), 475–488. https://doi.org/10.1016/S0002-9440(10)62991-4 

[11]. Desmoulière, A., Guyot, C., & Gabbiani, G. 2004, The stroma reaction myofibroblast: a key player in the control of tumor cell behavior. The International journal of developmental biology, 48(5-6), 509–517. https://doi.org/10.1387/ijdb.041802ad

[12]. Kang, N., Shah, V. H., & Urrutia, R. 2015, Membrane-to-Nucleus Signals and Epigenetic Mechanisms for Myofibroblastic Activation and Desmoplastic Stroma: Potential Therapeutic Targets for Liver Metastasis?. Molecular cancer Research MCR, 13(4), 604–612. https://doi.org/10.1158/1541-7786.MCR-14-0542 

[13]. Catteau, X., Simon, P., & Noël, J. C. 2014, Myofibroblastic reaction is a common event in metastatic disease of breast carcinoma: a descriptive study. Diagnostic pathology, 9, 196. https://doi.org/10.1186/s13000-014-0196-6

[14]. Muir, A. B., Dods, K., Noah, Y., Toltzis, S., Chandramouleeswaran, P. M., Lee, A., Benitez, A., Bedenbaugh, A., Falk, G. W., Wells, R. G., Nakagawa, H., & Wang, M. L. 2015, Esophageal epithelial cells acquire functional characteristics of activated myofibroblasts after undergoing an epithelial to mesenchymal transition. Experimental cell research, 330(1), 102–110. https://doi.org/10.1016/j.yexcr.2014.08.026

[15]. Desmoulière, A., Guyot, C., & Gabbiani, G. 2004, The stroma reaction myofibroblast: a key player in the control of tumor cell behavior. The International journal of developmental biology, 48(5-6), 509–517. https://doi.org/10.1387/ijdb.041802ad

[16]. Blonska, M., Agarwal, N. K., & Vega, F. 2015. Shaping of the tumor microenvironment: Stromal cells and vessels. Seminars in cancer biology, 34, 3–13. https://doi.org/10.1016/j.semcancer.2015.03.002

[17]. Kellermann, M. G., Sobral, L. M., da Silva, S. D., Zecchin, K. G., Graner, E., Lopes, M. A., Nishimoto, I., Kowalski, L. P., & Coletta, R. D. 2007, Myofibroblasts in the stroma of oral squamous cell carcinoma are associated with poor prognosis. Histopathology, 51(6), 849–853. https://doi.org/10.1111/j.1365-2559.2007.02873.x

[18]. van Kempen, L. C., Ruiter, D. J., van Muijen, G. N., & Coussens, L. M. 2003, The tumor microenvironment: a critical determinant of neoplastic evolution. European journal of cell biology, 82(11), 539–548. https://doi.org/10.1078/0171-9335-00346

[19]. Kalluri, R., & Zeisberg, M. 2006, Fibroblasts in cancer. Nature reviews. Cancer, 6(5), 392–401. https://doi.org/10.1038/nrc1877

[20]. Zidar, N., Gale, N., Kambic, V., & Fischinger, J. 2002, Proliferation of myofibroblasts in the stroma of epithelial hyperplastic lesions and squamous carcinoma of the larynx. Oncology, 62(4), 381–385. https://doi.org/10.1159/000065071

[21]. Lynch, C. C., & Matrisian, L. M. 2002, Matrix metalloproteinases in tumor-host cell communication. Differentiation; research in biological diversity, 70(9-10), 561–573. https://doi.org/10.1046/j.1432-0436.2002.700909.x

[22]. Prime, S. S., Davies, M., Pring, M., & Paterson, I. C. 2004. The role of TGF-beta in epithelial malignancy and its relevance to the pathogenesis of oral cancer (part II). Critical reviews in oral biology and medicine: an official publication of the American Association of Oral Biologists, 15(6), 337–347. https://doi.org/10.1177/154411130401500603

[23]. Maeda, G., Chiba, T., Okazaki, M., Satoh, T., Taya, Y., Aoba, T., Kato, K., Kawashiri, S., & Imai, K. 2005, Expression of SIP1 in oral squamous cell carcinomas: implications for E-cadherin expression and tumor progression. International journal of oncology, 27(6), 1535–1541.

[24]. Silzle, T., Randolph, G. J., Kreutz, M., & Kunz-Schughart, L. A. 2004, The fibroblast: sentinel cell and local immune modulator in tumor tissue. International journal of cancer, 108(2), 173–180. https://doi.org/10.1002/ijc.11542

[25]. Olaso, E., Santisteban, A., Bidaurrazaga, J., Gressner, A. M., Rosenbaum, J., & Vidal-Vanaclocha, F. 1997, Tumor-dependent activation of rodent hepatic stellate cells during experimental melanoma metastasis. Hepatology (Baltimore, Md.), 26(3), 634–642. https://doi.org/10.1002/hep.510260315

[26]. David, L., Dulong, V., Coquerel, B., Le Cerf, D., Cazin, L., Lamacz, M., & Vannier, J. P. 2008, Collagens, stromal cell-derived factor-1alpha and basic fibroblast growth factor increase cancer cell invasiveness in a hyaluronan hydrogel. Cell proliferation, 41(2), 348–364. https://doi.org/10.1111/j.1365-2184.2008.00515.x

[27]. Akagawa, S., Ohuchida, K., Torata, N., Hattori, M., Eguchi, D., Fujiwara, K., Kozono, S., Cui, L., Ikenaga, N., Ohtsuka, T., Aishima, S., Mizumoto, K., Oda, Y., & Tanaka, M. 2014, Peritoneal myofibroblasts at metastatic foci promote dissemination of pancreatic cancer. International journal of oncology, 45(1), 113–120. https://doi.org/10.3892/ijo.2014.2391

[28]. Yeung, T. M., Buskens, C., Wang, L. M., Mortensen, N. J., & Bodmer, W. F. (2013). Myofibroblast activation in colorectal cancer lymph node metastases. British journal of cancer, 108(10), 2106–2115. https://doi.org/10.1038/bjc.2013.209

[29] Rukmini, D., Kannan, B., Pandi, C., Pandi, A., Prasad, P., Jayaseelan, V. P., & Arumugam, P., 2024,  Aberrated PSMA1 expression associated with clinicopathological features and prognosis in oral squamous cell carcinoma. Odontology, 112(3), 950–958. https://doi.org/10.1007/s10266-023-00883-0

[30] Kannan, B., Pandi, C., Pandi, A., Jayaseelan, V. P., & Arumugam, P., 2024,  Triggering receptor expressed in myeloid cells 1 (TREM1) as a potential prognostic biomarker and association with immune infiltration in oral squamous cell carcinoma. Archives of oral biology, 161, 105926. https://doi.org/10.1016/j.archoralbio.2024.105926

[31] Ramasubramanian, A., Ramani, P., Kannan, B., & Arumugam, P., 2023, High expression of novel biomarker TBRG4 promotes the progression and invasion of oral squamous cell carcinoma. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology, 52(8), 738–745. https://doi.org/10.1111/jop.13470