Open Access
Volume 7, Number 4, December 2017
Article Number 21
Number of page(s) 3
Published online 13 November 2017

© Author(s) 2017. This article is published with open access by China Medical University

Licence Creative Commons
Open Access This article is distributed under terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided original author(s) and source are credited.

Cancer is an umbrella term used to designate a number of diseases originating from oncogenic tissues that overcome the normal cellular mechanisms by overexpressing self-renewal and resisting growth inhibiting and death promoting signals. Cancer is recognized as a chronic, non-healing wound that strikes millions of lives around the globe.[1] Based on the WHO cancer statistics, approximately 14.1 million newly diagnosed cases and 8.2 million deaths were accounted to cancer in 2012. Further, the incidence of cancer is gauged to rise exponentially by 70% over upcoming two decades.[2] The globalization of cancer is prominently the consequence of adopting cancer-enriching, modernized lifestyle patterns such as substance abuse (smoking and alcohol use), cessation of physical activity and unhealthy dietary habits (low fruit and vegetable intake).[3] The impact of cancer extends beyond the physical and psychological realms with significant financial consequences. In addition, it enormously influences the quality of life (QoL); as a consequence the behavior of cancer patients and their family member’s decisions with regard to their treatment. [4, 5]

Metastasis entails a complex cascade of cellular and molecular events that mediate cancer cells to circulate and form secondary niche within distant tissue systems through ongoing bidirectional interaction with the host microenvironment in a manner that is conducive to survival and proliferation of cancer cells. [6] The expression of necessary characteristics such as genetic and epigenetic instability, presence of cancer stem cells, immunoevasive self-defenses, positive interaction with foreign (host) microenvironments, sustained cell cycles and chemotherapeutic antagonism sets in motion the lethal phenotypic facet of cancer; metastasis.[7, 8] Metastasis contributes to nearly 90% of cancer related deaths.[9] Patients who are diagnosed with cancers that are metastatic at presentation tend to have poor outcomes; an improved understanding of this phenomenon might provide an additional prognostic marker. Furthermore, the poor outcomes for these patients emphasize the importance of deciphering biological pathways contributing to metastasis as a means for developing novel anti-metastatic therapies. Nonetheless, the underlying molecular mechanisms governing these interactions are yet to be deciphered.

Since the discovery of Trousseau’s syndrome in 1865, platelets have been extensively trialed for their potential in advancing cancer through metastasis.[10] Platelets, besides their established role in hemostasis and thrombosis, facilitate tumor invasiveness upon activation. The reciprocity of cancer cells and platelets is critical for development of cancer metastasis. Review studies supports the published evidence that thrombocytosis is directly proportional to the increased propensity of cancer cells to express metastatic behavior and poor prognosis and life expectancy among cancer patients.[11] Studies have also documented that formation of 'platelet cloak' around cancer cells to evade immune cell cytotoxic lysis is at the mercy of activated platelets. Additionally, platelet releasates carry diverse vasogenic, mitogenic and chemotactic factors that nurture the tumor growth and support metastasis.[12] Likewise, platelets have also been implicated to gather leukocytes through chemical signals at the site of platelet-cancer cell interaction, thereby mediating smooth survival of tumor in vascular compartment and penetration to distant organs. [13]

Mucins, biochemically, are abundantly glycosylated proteins of high molecular weight with defining feature of serine and threonine amino acid tandem repeats.[14] The promising physiological functions of mucins such as cellular differentiation, cellular adhesion, cellular signaling and immune regulation make them an important part of proteomics research.[15] Conversely, their deviant expression in diseased states including inflammatory and cancerous conditions has been well reported on several occasions.[16-18] Mucins expressing human carcinomas are prone to increased metastasis and foreshadow poor clinical outcomes.[19] With the major breakthrough in molecular attributes of cancer, mucins and their association with platelet activation and cancer metastasis has assembled a lot of awareness over past few years.

Cancer cells expressing abnormal cell surface molecules, specifically the altered mucin glycoproteins are remarkable for their interaction with E, L and P-selectins. Notably, selectins also carry the potential to recognize and bind the altered carbohydrate molecules expressed by cancer cells. Certainly, such associations allow cancer cells to interact with blood borne cells including endothelial cells, leukocytes and platelets and mediate their aggressive metastatic phenotype.[20-22] Previous studies have attempted to ascertain the link between the trio of mucin, platelets and metastasis.

Platelets can be activated by mucins in a selectin-dependent manner, emphasizing the importance of mucin-selectin interaction, P and L-selectins in particular. The proposed mechanism of platelet activation by mucin is indirect and facilitated by leukocytes via interaction with L-selectin. P-selectins and their role in cancer metastasis have been the subject of extensive research over the last few years with P-selectin expression demonstrated in activated platelets.[23, 24] Furthermore, the ability of P-selectins to aggregate platelets cannot be underestimated.[25-27] A literature review suggested both in vivo and in vitro interaction of platelets with cancer derived mucins reliant on P-selectin availability. In addition, the platelet-mucin interaction without external thrombin utilization is supported by in vivo observation. Experimental removal of mucin from cancer cell lines significantly reduces the strength of metastasis and studies have demonstrated that tumor cell-platelet aggregation as well as establishment of tumor metastasis was attenuated in P-selectin-deficient mice.[28] This demonstrates the crucial role of hidden molecular pathways harmonized by cancer derived mucins to augment the metastatic process. Despite these exciting strides made over the last two decades, the precise mechanism of mucin platelet interaction and their role in cancer metastasis remains to be ascertained.

1. Conclusion

Taken together, metastasis still represents the major cause of cancer related mortality. Unfortunately, the concealed molecular pathways guiding the primary tumors to invade distant organs remain to be elucidated. Mucin, until recently, is emerging as a new accessory source for cancer to unfurl their metastatic terror. Screening of tumor with metastatic constitution is a growing concern and demands aggressive measures to attenuate its negative prognostic impact on active cases. On this account, experimental analysis will be of immense value to identify the intensity and precision of mucin contribution towards metastasis and its sensitivity and specificity both as prognostic and diagnostic molecular marker. A step towards development of accurate and reliable relationship among mucin, platelets and metastasis will eventually yield unprecedented new insights into the future therapy.

Conflicts of Interest Statement

The authors disclose no conflicts of interest.


  1. Riss J, Khanna C, Koo S, Chandramouli GV, Yang HH, Hu Y, et al. Cancers as wounds that do not heal: differences and similarities between renal regeneration/repair and renal cell carcinoma. Cancer Res 2006; 66: 7216-24. [CrossRef] [Google Scholar]
  2. Cancer Research UK. Worldwide Cancer Statistics. 2016. Accessed 18/09/2016. [Google Scholar]
  3. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011, 61: 69-90. [CrossRef] [PubMed] [Google Scholar]
  4. Callahan, C,Brintzenhofeszoc K. Financial Quality of Life for Patients With Cancer: An Exploratory Study. J Psychosoc Oncol. 2015, 33: 377-94. [CrossRef] [Google Scholar]
  5. Heydarnejad MS, Hassanpour DA, Solati DK. Factors affecting quality of life in cancer patients undergoing chemotherapy. Afr Health Sci. 2011, 11: 266-70. [PubMed] [Google Scholar]
  6. Khan, N, Mukhtar H. Cancer and metastasis: prevention and treatment by green tea. Cancer Metastasis Rev. 2010, 29: 435-45. [CrossRef] [PubMed] [Google Scholar]
  7. Chiang AC, Massagué J. Molecular Basis of Metastasis. N Engl J Med. 2008, 359: 2814-23. [CrossRef] [PubMed] [Google Scholar]
  8. Steeg PS. Targeting metastasis. Nature Reviews Cancer. 2016, 16:201-201. [CrossRef] [PubMed] [Google Scholar]
  9. Lou XL, Sun J, Gong SQ, Yu XF, Gong R, Deng H. Interaction between circulating cancer cells and platelets: clinical implication. Chin J Cancer Res. 2015, 27: 450-60. [PubMed] [Google Scholar]
  10. Varki, A. Trousseau’s syndrome: multiple definitions and multiple mechanisms. Blood. 2007, 110: 1723-9. [CrossRef] [PubMed] [Google Scholar]
  11. Sharma, D,Brummel-Ziedins KE, Bouchard BA, Holmes CE. Platelets in tumor progression: a host factor that offers multiple potential targets in the treatment of cancer. J Cell Physiol. 2014, 229: 1005-15. [CrossRef] [PubMed] [Google Scholar]
  12. Li, N. Platelets in cancer metastasis: To help the “villain” to do evil. Int J Cancer. 2016, 138: 2078-87. [CrossRef] [PubMed] [Google Scholar]
  13. Labelle, M,Begum S, Hynes RO. Platelets guide the formation of early metastatic niches. Proc Natl Acad Sci U S A. 2014, 111: E3053-61. [CrossRef] [PubMed] [Google Scholar]
  14. Voynow JA, Rubin BK. Mucins, mucus, and sputum. Chest. 2009, 135: 505-12. [CrossRef] [PubMed] [Google Scholar]
  15. Rachagani, S,Torres MP, Moniaux N, Batra SK. Current status of mucins in the diagnosis and therapy of cancer. Biofactors. 2009, 35: 509-27. [CrossRef] [PubMed] [Google Scholar]
  16. Wang RQ, Fang DC. Alterations of MUC1 and MUC3 expression in gastric carcinoma: relevance to patient clinicopathological features. J Clin Pathol. 2003, 56: 378-84. [CrossRef] [PubMed] [Google Scholar]
  17. Duncan TJ, Watson NF, Al-Attar AH, Scholefield JH, Durrant LG. The role of MUC1 and MUC3 in the biology and prognosis of colorectal cancer. World J Surg Oncol. 2007, 5: 31. [CrossRef] [PubMed] [Google Scholar]
  18. Choi JS, Lee KMA, Lee HE, Lee HS, Kim WH. Mucinous gastric carcinomas. Cancer. 2009, 115: 3581-90. [CrossRef] [PubMed] [Google Scholar]
  19. Borsig, L,Wong R, Feramisco J, Nadeau DR, Varki NM, Varki A. Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proc Natl Acad Sci U S A. 2001, 98: 3352-7. [CrossRef] [PubMed] [Google Scholar]
  20. Varki, A. Trousseau’s syndrome: multiple definitions and multiple mechanisms. Blood. 2007, 110: 1723-9. [CrossRef] [PubMed] [Google Scholar]
  21. Fukuda, M. Possible roles of tumor-associated carbohydrate antigens. Cancer Res. 1996; 56: 2237-44. [Google Scholar]
  22. Varki, N.M., Varki, A. Semin. Thromb. Hemostasis, in press. 2002. [Google Scholar]
  23. Kansas GS. Selectins and their ligands: current concepts and controversies. Blood. 1996, 88: 3259-87. [Google Scholar]
  24. Varki, A. Selectin ligands. Proc. Natl. Acad. Sci. U. S. A. 1994, 91:7390-7390. [CrossRef] [PubMed] [Google Scholar]
  25. Evangelista, V,Manarini S, Sideri R, Rotondo S, Martelli N, Piccoli A. et al. Platelet/polymorphonuclear leukocyte interaction: P-selectin triggers protein-tyrosine phosphorylation-dependent CD11b/CD18 adhesion: role of PSGL-1 as a signaling molecule. Blood. 1999, 93:876-876. [Google Scholar]
  26. Hidari KI, Weyrich AS, Zimmerman GA, McEver RP. Engagement of P-selectin glycoprotein ligand-1 enhances tyrosine phosphorylation and activates mitogen-activated protein kinases in human neutrophils. J. Biol. Chem. 1997; 272: 28750-6. [CrossRef] [PubMed] [Google Scholar]
  27. Merten, M, Thiagarajan P. Role for sulfatides in platelet aggregation. Circulation. 2001, 104: 2955-60. [CrossRef] [PubMed] [Google Scholar]
  28. Kim YJ, Borsig L, Varki NM, Varki A. P-selectin deficiency attenuates tumor growth and metastasis. Proc Natl Acad Sci U S A. 1998,95: 9325-30. [CrossRef] [PubMed] [Google Scholar]