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Polish Journal of Pathology
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Original paper

Association of infiltrating cells with microvessel density in oral squamous cell carcinoma

Olga Stasikowska-Kanicka
,
Małgorzata Wągrowska-Danilewicz
,
Marian Danilewicz

Pol J Pathol 2017; 68 (1): 40-48
Online publish date: 2017/05/23
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Introduction

Oral cavity squamous cell carcinoma (OSCC) is a malignant neoplasia arising from the oral mucosal epithelium [1]. Oral cancer is the sixth most common cancer worldwide and remains a serious problem of public health in the developing countries.
Several lines of evidence indicate that immune cells in the tumor microenvironment play an important role in regulating tumor progression, which may determine the clinical parameters and prognosis [2, 3, 4, 5, 6]. Macrophages have been implicated as key contributors to the tumor-microenvironment dynamics [7]. Nearly all tissues contain resident macrophages which undergo tissue-specific adaptations that facilitate their contributions towards maintaining tissue homeostasis and/or tissue-specific functions [8]. Tumor-associated macrophages (TAMs) can derive from blood monocytes or can be differentiated from resident tissue macrophages. Tumor-associated macrophages are closely involved in tumorigenesis by inducing angiogenesis, immunosuppression, and invasion. They also play an important role in tumor cell migration and metastasis [9]. Several reports have suggested that TAMs are associated with tumor growth, disease progression, and poor prognosis in some human cancers [2, 10].
Mast cells derive from hematopoietic progenitor cells and migrate into vascularized tissues, in which they differentiate into mature cells. The wide range of biological function, ubiquitous distribution and strategic location near blood vessels, nerves, inflamed tissues and neoplastic foci enable mast cells to play a central role in a multitude of physiologic, immunologic and pathologic processes [11]. Mast cells are involved in pain, tissue damage as well as repair and allergic inflammatory reactions and contribute to the pathogenesis of a number of disorders (e.g. asthma, rhinitis, tissue remodeling, arthritis, anaphylaxis) [12, 13]. Recently, apart from their roles in the maintenance of homeostasis and in inflammation, the association of mast cells with various tumors has been described [14]. In several malignancies, mast cell density has been found to correlate with increased risk of metastasis and poor prognosis [3, 4]. Mast cell activity facilitating tumorigenesis includes production of factors that support the process of forming a new vascular system within the site of neoplastic involvement.
Dendritic cells (DCs) are a heterogeneous population of highly motile cells that originate from the precursors in the bone marrow. DCs control immune responses and are pivotal in the development of immune memory and tolerance. Malfunction of DCs contributes to diseases such as autoimmunity, allergy, and cancer. DCs may induce and maintain the antitumor immunity. DCs infiltrating primary tumors (TIDCs) play an important role in antitumor immune surveillance, as TIDCs migrating to the regional lymph nodes are capable of presenting tumor antigens to naïve tumor-specific T cells. On the other hand, in malignant tumors, DCs display different phenotype and activity with pro-tumorigenic functions as well. DCs may lose antigen-presenting activity in the tumor environment or polarize into immunosuppressive regulatory DCs, which suppress effector T cells and support tumor growth [15]. Dendritic Langerhans cells (LCs) are a subset of DCs present in skin and mucosal linings, providing immunosurveillance to these tissue compartments [16]. In the oral mucosa, an important role of LCs in evoking the antitumoral response may be expected, although no definite proofs have been provided.
Natural killer (NK) cells are a heterogeneous population of lymphocytes originating from a distinct developmental lineage [17], and are functionally characterized by their cytotoxicity and cytokine production. NK cells belong to the innate immune system, and they can react to rapid changes in host cells without prior sensitization. As part of the first line of defense, they recognize and lyse virally infected cells and tumor cells. NK cells are not only killer cells, but they also have the capacity to shape adaptive immunity by regulating T cell responses [18, 19]. NK cells can be beneficial for mounting a T cell response by modulating DC function. NK cells act by different mechanisms depending on the DC subsets and the prevailing cytokine environment. Natural killer T (NKT) cells can modulate immune responses in autoimmunity, infections and malignancies [20]. Several studies have demonstrated important anti-tumor effects of NKT cells and have reported reduced numbers of NKT cells in patients with malignant diseases, including malignant melanoma, head and neck, breast, colon and renal cancer [5].
The tumor microenvironment is emerging as a crucial aspect in the progression of solid and hematological malignancies. In this context, macrophages and mast cells have been demonstrated to have a role in enhancing angiogenesis in cancer through the release of pro-angiogenic factors and through a complex cross-talk within the tumor microenvironment [6].
Therefore, the objectives of this study were to evaluate the abundance of NKT cells (CD56 positive), mucosal dendritic cells (langerin positive), macrophages (CD68 positive), mast cells (tryptase positive), and microvessel density (CD31 positive areas) in relation to patient outcomes. Another purpose was to find a possible association between investigated cellular populations and microvessel density.

Material and methods

Patients

Seventy-eight formalin-fixed, paraffin-embedded tissue specimens of oral squamous cell carcinoma (OSCC), and eighteen control cases (non-cancer mucosa originating from the Plastic and Reconstructive Surgery Department) were retrieved from archival material (Chair of Pathomorphology, Medical University of Lodz, Poland). Paraffin-embedded tissue sections taken from postoperative material were diagnosed using standard hematoxylin and eosin staining, and the histological diagnoses were established according to the current standards [21]. The main criteria for patient selection were histopathological similarities within the group (G2), and the same anatomical localization of lesions (the floor of the mouth). To find the possible relationship between the studied markers and clinical prognosis, patients with OSCC were additionally divided into two groups: with better prognosis – OSCCBP (oral squamous cell carcinoma – better prognosis) (OSCC without metastatic disease, n = 37), and with poorer prognosis – OSCCPP (oral squamous cell carcinoma – poorer prognosis) (OSCC with metastases to regional lymph nodes and/or with distant metastases, n = 41). The age range for the OSCCBP group was from 28 to 75 years (mean ± SD = 59.24 ± 10.89), for the OSCCPP group was from 40 to 84 (mean ± SD = 59.39 ± 11.16) and for control cases 15 to 74 (mean ± SD = 47.05 ± 18.71).

Immunohistochemistry

Formalin-fixed paraffin-embedded, 3-µm tissue sections were mounted onto SuperFrost slides (SuperFrost Plus, Gerhord Menzel GmbH, Braunschweig, Germany), and deparaffinized in xylene and ethanol of graded concentrations. For antigen retrieval, the slides were treated in a microwave oven in a solution of TRS (Target Retrieval Solution, High pH, Dako, Denmark) for 30 minutes (2 × 6 minutes 360 W, 2 × 5 180 W, 2 × 4 minutes 90 W). After cooling down at room temperature, they were transferred to 0.3% hydrogen peroxide in methanol, for 30 minutes, to block endogenous peroxidase activities. Sections were rinsed with Tris-buffered saline (TBS, Dako, Denmark) and incubated for 30 minutes with monoclonal mouse primary antibodies against: CD68 (Dako; clone: PG-M1, dilution 1 : 100), mast cell tryptase (Dako; clone: AA1, dilution 1 : 100), CD31 (Dako; clone: JC70A, dilution 1 : 40), CD56 (Dako; clone: 123C3, dilution 1 : 50) and 60 minutes with rabbit polyclonal to langerin (Abcam; clone: EPR15863, dilution 1 : 1000). Immunoreactive proteins were visualized using the appropriate EnVision-HRP kit (Dako, Carpinteria, CA, USA) according to the instructions of the manufacturer. Visualization was performed by incubating the sections in a solution of 3,3’-diaminobenzidine (Dako, Denmark). After washing, the sections were counterstained with Mayer’s hematoxylin and mounted. For each antibody and for each sample, a negative control was processed. Negative controls were carried out by incubation in the absence of the primary antibody and always yielded negative results.

Morphometry

Morphometric analysis of CD68, CD56, langerin and mast cell tryptase positive cells

CD68, CD56, langerin and mast cell tryptase positive cells were evaluated using a computer image analysis system consisting of a PC equipped with a Pentagram graphic tablet, Indeo Fast card (frame grabber, true-color, real-time), produced by Indeo (Taiwan), and a color TV camera Panasonic (Japan) coupled with a Carl Zeiss microscope (Germany). This system was programmed (MultiScan 18.03 software, produced by Computer Scanning Systems, Poland) to calculate the number of objects (semiautomatic function).
The number of CD68, CD56, langerin and mast cell tryptase positive cells was estimated by counting all positive cells in 7-10 high power monitor fields (HPF) (0.029 mm² each), marking immunopositive cells (semiautomatic function).

Morphometric analysis of microvessel density

Microvessel density (CD31 positive areas) was evaluated using the same computer image analysis system as described above. CD31 immunostains were evaluated in the vessels only (not in the individual cells), in the most vascular areas. The results were presented as the mean number of CD31 positive vessels with visible lumina per HPF (0.029 mm²).

Statistical methods

Differences between groups were tested using unpaired Student’s t-test preceded by evaluation of normality and Levene’s test. The Mann-Whitney U test was used where appropriate. Correlation coefficients were calculated using Spearman’s method. Results were considered statistically significant if p < 0.05.

Results

The quantitative data of the immunoexpression of tryptase, langerin, CD68, CD56 positive cells and microvessel density are presented in Table I.
The mean number of CD68 positive cells was significantly higher in the OSCCPP group (Fig. 1.IA) in comparison to both OSCCBP (Fig. 1.IB) and control groups (Fig. 1.IC). We also found a significantly lower mean number of tryptase positive mast cells in OSCCPP (Fig. 1.IIA) compared to OSCCBP (Fig. 1.IIB). The mean number of langerin positive dendritic cells was significantly decreased in the OSCCPP group (Fig. 2.IA) in comparison to both OSCCBP (Fig. 2.IB), and control groups (Fig. 2.IC). The mean number of CD56 positive cells was lower in the OSCCPP group (Fig. 2.IIA) in comparison to both OSCCBP (Fig. 2.IIB) and control groups (Fig. 2.IIC), but there were no statistically significant differences between the mean numbers of CD56 positive cells in tested groups. The mean number of the vessels was significantly higher in the OSCCPP group (Fig. 3A) in comparison to OSCCBP (Fig. 3B) and control groups (Fig. 3C). We also found a significantly higher mean number of vessels in OSCCBP compared to the control group.
In both OSCCPP and OSCCBP groups there were positive significant correlations between the number of Langerhans dendritic cells and CD56 positive NK cells as well as tryptase positive mast cells, whereas the correlations between the number of Langerhans dendritic cells and CD68 positive cells were not statistically significant (Table II).
In the OSCCBP group there were positive significant correlations between the microvessel density and the number of CD68 positive macrophages and tryptase positive mast cells. In the OSCCPP group there were positive significant correlations between the microvessel density and the number of CD68 positive macrophages. We also found a negative correlation between the microvessel density and the number of tryptase positive mast cells and Langerhans dendritic cells in the OSCCPP group (Table III).
In the control group all these correlations were weak and not significant (data not shown).

Discussion

Tumors are not made up of a single cell type but are comprised of a mixture of cells of different lineages, including malignant cells but also innate and adaptive immune cells, fibroblasts, endothelial cells, and others. These cells have a double-edged sword function, being involved both in tumor suppression and in tumor progression and metastasis [22, 23]. Therefore, a better understanding of their role may aid further research in order to develop novel targeted therapies.
Tumor-associated macrophages are the predominant inflammatory components of immune cell infiltration in cancer stroma, which is discovered in the tumor microenvironment of many cancers [24]. Several reports have suggested that TAMs are associated with tumor initiation and development, immunosuppression, stroma formation, angiogenesis, invasion, and metastasis [6, 25, 26]. Studies in various cancers have shown that TAMs can be associated with both positive and negative prognosis [27]. In our study the mean number of CD68 positive cells was significantly higher in the OSCCPP group in comparison to both OSCCBP and control groups. Literature data show that patients with high TAM count tumors have a significantly more aggressive phenotype than those with low TAM count tumors [28, 29, 30]. In this context, our results seem to be in agreement with other findings. For instance, Ishigami et al. reported that patients with a high TAM count had poorer overall survival than those with a low TAM count [31].
Numerous experiments have demonstrated negative prognostic effect for mast cells, concluding that high mast cell density is related to increased risk of metastasis, poor prognosis and lower overall survival [32]. In contrast to these findings, we found a significantly lower mean number of tryptase positive mast cells in OSCCPP compared to OSCCBP. Similarly to our study, Jiang et al. found that a low mast cell count was associated with worse prognosis in gastric cancer [33]. Liu et al. reported that higher infiltration of mast cells is inversely associated with depth of invasion and lymph node status [34]. In some tumors such as breast cancer, mast cells seem to exert anti-tumor effects and are associated with favorable prognosis, whereas in some tumors such as non-small cell lung carcinoma the role of mast cells is still controversial [35]. We postulate that mechanisms underlying the mast cells’ anti- and pro-tumoral activity still remain to be fully understood. In accordance with previous studies we also speculate that mast cells anti-tumor function may reflect their ability to mediate direct tumor killing, whereas their pro-tumoral effect is related to promotion of tissue remodeling, immunomodulation and production of pro-angiogenic factors [36, 37].
Infiltration of DCs into primary tumor lesions is associated with significantly prolonged patient survival and reduced incidence of metastatic disease in patients with oral, head and neck, nasopharyngeal, lung, bladder, esophageal, and gastric carcinomas [38]. In our study, high density of mucosal dendritic cells expressing the langerin marker was associated with significantly better prognosis. In agreement with our study, Ishigami et al. reported that the survival of patients with a high dendritic cell count was significantly better than in those with a low dendritic cell count [39]. Moreover, Tsujitani et al. [40] showed in gastric cancer that in cases with higher dendritic cell infiltration, survival time was significantly longer and peritoneal recurrences were rarer than in cases with only a slight infiltration. We also observed a significant correlation between number of Langerhans cells and tryptase positive mast cells in both tested groups of cancer. Interactions between these cells are not widely investigated, especially in the context of tumoral tissues [41]. According to literature data, mast cells influence dendritic cell migration, maturation, and function by releasing TNF- (tumor necrosis factor), histamine, and prostaglandin E2 and D2. It has been shown that the relationship between mast cells and DCs may contribute either to pro-inflammatory and anti-tumoral activity by release of IL-12 and IL-6 by DCs, or to immunosuppression and pro-tumoral function via IL-10 production, among others [36, 42].
In the context of tumor immunity, NKT cells are usually associated with antitumor responses, and the number of NK cells is positively associated with the prognosis and the survival time [39, 43]. In our study, among all four investigated immune cells, NK cells were the most scanty population of infiltrating cells. In accordance with previous findings, in our study, the number of NK cells was also higher in the OSCCBP group compared to the OSCCPP group, but the difference was not statistically significant. A possible explanation for the lack of significance may be the small number of tested cases, but it is also possible that technical reasons may be responsible for our results.
We revealed statistically significant correlations between the number of NK cells and Langerhans cells in both tested groups of cancer. We assume that NK cells may have a prognostic role due to their close interaction with antigen-presenting cells such as Langerhans cells. It has been shown that DCs mediate NK cell activation during innate immune responses, e.g. by improving survival, interferon  secretion and cytotoxic activity of NK cells. On the other hand, NK cells have the ability to promote DCs’ maturation and aid them to initiate adaptive immunity (e.g. against tumoral cells) via T-cell stimulation and differentiation. Interaction between these two immune cell populations is still under investigation [44, 45, 46].
Several studies have demonstrated correlations between tumor-associated macrophages, mast cells and microvessel density in different malignancies [47, 48, 49, 50]. In recent years, many findings have confirmed that mast cell accumulation correlates with increasing density of microvessels [51]. Mast cell activity facilitating tumorigenesis includes production of factors that support the process of forming a new vascular system within the site of tumor formation. Mast cell proangiogenic factors include VEGF (vascular endothelial growth factor), bFGF (basic fibroblast growth factor), TNF- (transforming growth factor ), TNF-, IL-8, metalloproteinases, tryptase and chymase. Our results also indicated a statistically significant association between the presence of mast cells and the process of angiogenesis. We found a negative correlation between the microvessel density and the number of tryptase positive mast cells in the OSCCPP group and a positive correlation between these parameters in the OSCCBP group. Further studies of the molecular mechanism of actions of mast cells are needed to better understand their role in angiogenesis.
It is well known that monocytes are continually recruited into tumors, differentiate into TAMs, accumulate in hypoxic areas, and may induce angiogenesis through secretion of angiogenic cytokines [52, 53]. Tumor-associated macrophages secrete numerous proangiogenic factors, such as VEGF, bFGF, and MMP9 (matrix metalloproteinase), which are all associated with tumor angiogenesis and metastasis [25]. The strong correlation between TAM infiltration and microvessel density described in both tested groups of cancer is in concordance with current knowledge in this field. Moreover, recent studies have shown that tumor and immune cells including TAMs release lymphangiogenic factors into the tumor microenvironment [54]. Thus, macrophages seem to be essential angiogenic and metastatic promoters that act both to prepare sites for metastatic cells and to promote extravasation and growth of metastases [55].
Here, we demonstrated a correlation between the number of Langerhans cells and density of tumor vessels. Data concerning the relationship between dendritic cells and angiogenesis are rather scanty. Martinet et al. suggested that DCs may contribute to the formation of tumor vessels in human breast tumors through lymphotoxin- production [56]. These authors observed that the density of DC clusters was strongly correlated with the density of tumor vessels and favorable clinical outcome. Moreover, it has been shown in ovarian carcinoma that tumor-associated plasmacytoid DCs are able to induce angiogenesis in vivo by producing TNF- and IL-8 [57]. On the other hand, recent studies have shown that VEGF inhibits the maturation and function of dendritic cells, and its expression negatively correlated with the number of DCs in tumors [58]. VEGF is thus suggested to be associated not only with the enhancement of angiogenesis, but also with a decline of local immune response in tumors. Decreased number of DCs in the OSCCPP group and a significant correlation between the number of langerin positive cells and the density of microvessels are coherent and could support this hypothesis. Although previous results suggest a relationship between DCs and angiogenesis within tumors, we cannot exclude the alternative possibilities that DCs arriving via tissue lymphatics may preferentially be attracted to pre-existing vessels. Further studies of the relationship between the number and activity of Langerhans cells and microvessel density are needed to better understand their role in oral carcinogenesis.
To the best of our knowledge, this is the first study considering the extent of tumor infiltration by four types of immune cells and microvessel density. The present study revealed an association between increased number of macrophages, decreased number of mast cells, Langerhans dendritic cells as well as NK cells and poorer prognosis of OSCC patients. Moreover, our findings suggest that the infiltrating cells (macrophages, Langerhans and mast cells) may be involved in angiogenesis. Further research is required to determine the underlying mechanisms by which these immune cells play a role in oral tumorigenesis. In particular, the understanding of the importance of these cells for microvessel development may serve as a potential therapeutic strategy.

This work was supported by a grant of the Medical University of Lodz, no. 503/6-038-01/503-61-002.
The authors declare no conflict of interest.

References

1. Konkimalla VB, Suhas VL, Chandra NR, et al. Diagnosis and therapy of oral squamous cell carcinoma. Expert Rev Anticancer Ther 2007; 7: 317-329.
2. Pirilä E, Väyrynen O, Sundquist E, et al. Macrophages modulate migration and invasion of human tongue squamous cell carcinoma. PLoS One 2015; 10 (3): e0120895.
3. Yodavudh S, Tangjitgamol S, Puangsa-art S. Prognostic significance of microvessel density and mast cell density for the survival of Thai patients with primary colorectal cancer. J Med Assoc Thai 2008; 91: 723-732.
4. Elpek GO, Gelen T, Aksoy NH, et al. The prognostic relevance of angiogenesis and mast cells in squamous cell carcinoma of the oesophagus. J Clin Pathol 2001; 54: 940-944.
5. Motohashi S, Nakayama T. Clinical applications of natural killer T cell-based immunotherapy for cancer. Cancer Sci 2008; 99: 638-645.
6. Ribatti D. Mast cells and macrophages exert beneficial and detrimental effects on tumor progression and angiogenesis. Immunol Lett 2013; 152: 83-88.
7. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nature Med 2013; 19: 1423-1437.
8. Davies LC, Jenkins SJ, Allen JE, et al. Tissue-resident macrophages. Nature Immunol 2013; 14: 986-995.
9. Bostrom MM, Irjala H, Mirtti T, et al. Tumor-Associated macrophages provide significant prognostic information in urothelial bladder cancer. PLoS One 2015; 10: e0133552.
10. Kim S, Cho SW, Min HS, et al. The expression of tumor-associated macrophages in papillary thyroid carcinoma. Endocrinol Metab 2013; 28: 192-198.
11. Chang S, Wallis RA, Yuan L, et al. Mast cells and cutaneous malignancies. Mod Pathol 2006; 19: 149-159.
12. Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol 2011; 12: 1035-1044.
13. Kumar V, Sharma A. Mast cells: emerging sentinel innate immune cells with diverse role in immunity. Mol Immunol 2010; 48: 14-25.
14. Theoharides TC, Conti P. Mast cells: The Jekyll and Hyde of tumor growth. Trends Immunol 2004; 25: 235-241.
15. Ma Y, Shurin GV, Peiyuan Z, et al. Dendritic cells in the cancer microenvironment. J Cancer 2013; 4: 6-44.
16. Banchereau J, Briere F, Caux C, et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000; 18: 767-811.
17. Godfrey DI, Berzins SP. Control points in NKT-cell development. Nat Rev Immunol 2007; 7: 505-518.
18. Crouse J, Xu HC, Lang PA, et al. NK cells regulating T cell responses: mechanisms and outcome. Trends Immunol 2015; 36: 49-58.
19. Crome SQ, Lang PA, Lang KS, et al. Natural killer cells regulate diverse T cell responses. Trends Immunol 2013; 34: 342-349.
20. Taniguchi M, Seino K, Nakayama T. The NKT cell system: bridging innate and acquired immunity. Nat Immunol 2003; 4: 1164-1165.
21. Barnes L, Everson JW, Reichart P, et al. World Health Organization Classification of Tumours. Pathology and Genetics Head and Neck Tumours. IARC Press, Lyon 2005; 168-176.
22. Kumar V, Abbas AK, Fausto N, et al. Robbins and Cotran Pathologic Basis of Diseases (8th ed.) Saunders Elsevier, Philadelphia 2010; 184-197.
23. Witz IP, Levy-Nissenbaum O. The tumor microenvironment in the post-PAGET era. Cancer Lett 2006; 242: 1-10.
24. Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 2002; 196: 254-265.
25. Mantovani A, Sozzani S, Locati M, et al. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002; 23: 549-555.
26. Kim S, Cho SW, Min HS, et al. The expression of tumor-associated macrophages in papillary thyroid carcinoma. Endocrinol Metab (Seoul) 2013; 28: 192-198.
27. Zhang B, Zhang Y, Zhao J, et al. M2-polarized macrophages contribute to the decreased sensitivity of EGFR-TKIs treatment in patients with advanced lung adenocarcinoma. Med Oncol 2014; 31: 127.
28. Ohno S, Inagawa H, Dhar DK, et al. The degree of macrophage infiltration into the cancer cell nest is a significant predictor of survival in gastric cancer patients. Anticancer Res 2003; 23: 5015-5022.
29. Ohno S, Inagawa H, Dhar DK, et al. Role of tumor-associated macrophages (TAM) in advanced gastric carcinoma: the impact on FasL-mediated counterattack. Anticancer Res 2005; 25: 463-470.
30. Wu H, He ZL, Peng JJ, et al. Tumor-associated macrophages promote angiogenesis and lymphangiogenesis of gastric cancer. J Surg Oncol 2012; 106: 462-468.
31. Ishigami S, Natsugoe S, Tokuda K, et al. Tumor-associated macrophage (TAM) infiltration in gastric cancer. Anticancer Res 2003; 23: 4079-4083.
32. Ribatti D, Guidolin D, Marzullo A, et al. Mast cells and angiogenesis in gastric carcinoma. Int J Exp Pathol 2010; 91: 350-356.
33. Jiang ZA, Zhang ZZ, Luo HS, et al. Mast cell density and the context of clinicopathological parameters and expression of p185, estrogen receptor, and proliferating cell nuclear antigen in gastric carcinoma. World J Gastroenterol 2002; 8: 1005-1008.
34. Liu ZL, Zhao MQ, Hou G, et al. Effects of mast cell infiltration on the development and metastasis of gastric carcinoma. Di Yi Jun Yi Da Xue Xue Bao 2005; 25: 809-811.
35. Rajput AB, Turbin DA, Cheang MC, et al. Stromal Mast cells in invasive breast cancer are a marker of favourable prognosis: a study of 4,444 cases. Breast Cancer Res Treat 2008; 107: 249-257.
36. Maltby S, Khazaie K, McNagny KM. Mast cells in tumor growth: angiogenesis, tissue remodeling and immune-modulation. Biochim Biophys Acta 2009; 1796: 19-26.
37. Nechushtan H. The complexity of the complicity of mast cells in cancer. Int J Biochem Cell Biol 2010; 42: 551-554.
38. Lotze MT. Getting to the source: dendritic cells as therapeutic reagents for the treatment of patients with cancer. Ann Surg 1997; 226: 1-5.
39. Ishigami S, Natsugoe S, Tokuda K, et al. Clinical impact of intratumoral natural killer cell and dendritic cell infiltration in gastric cancer. Cancer Lett 2000; 159: 103-108.
40. Tsujitani S, Kakeji Z, Watanabe A, et al. Infiltration of dendritic cells in relation to tumor invasion and lymph node metastasis in human gastric cancer. Cancer 1990; 66: 2012-2016.
41. Otsuka A, Kubo M, Honda T, et al. Requirement of interaction between mast cells and skin dendritic cells to establish contact hypersensitivity. PLoS One 2011; 6: e25538.
42. Wasiuk A, de Vries VC, Hartmann K, et al. Mast cells as regulators of adaptive immunity to tumours. Clin Exp Immunol 2008; 155: 140-146.
43. Ishigami S, Natsugoe S, Tokuda K, et al. Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer 2000; 88: 577-583.
44. Brilot F, Strowig T, Munz C. NK cells interactions with dendritic cells shape innate and adaptive immunity. Front Biosci 2008; 13: 6443-6454.
45. Wehner R, Dietze K, Bachmann M, et al. The bidirectional crosstalk between human dendritic cells and natural killer cells. J Innate Immun 2011; 3: 258-263.
46. Chijioke O, Münz C. Dendritic cell derived cytokines in human natural killer cell differentiation and activation. Front Immunol 2013; 4: 365.
47. Ammendola M, Sacco R, Sammarco G, et al. Mast cells density positive to tryptase correlates with angiogenesis in pancreatic ductal adenocarcinoma patients having undergone surgery. Gastroenterol Res Pract 2014: 951957.
48. Leek RD, Hunt NC, Landers RJ, et al. Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer. J Pathol 2000; 190: 430-436.
49. Ullah NA, Ashraf EM. Angiogenesis and mast cell density as predictors of patient survival in squamous cell carcinoma of lung. J Cancer Res Ther 2013; 9: 701-705.
50. Wu H, Xu JB, He ZL, et al. Tumor-associated macrophages promote angiogenesis and lymphangiogenesis of gastric cancer. J Surg Oncol 2012; 106: 462-468.
51. Ammendola M, Sacco R, Donato G, et al. Mast cell positivity to tryptase correlates with metastatic lymph nodes in gastrointestinal cancer patients treated surgically. Oncology 2013; 85: 111-116.
52. Leek RD, Harris AL, Lewis CE. Cytokine networks in solid human tumors: regulation of angiogenesis. J Leukoc Biol 1994; 56: 423-435.
53. Leek RD, Lewis CE, Whitehouse R, et al. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 1996; 56: 4625-4629.
54. Riabov V, Gudima A, Wang N, et al. Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis. Front Physiol 2014; 5: 75.
55. Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 2010; 141: 52-67.
56. Martinet L, Filleron T, Le Guellec S, et al. High endothelial venule blood vessels for tumor-infiltrating lymphocytes are associated with lymphotoxin -producing dendritic cells in human breast cancer. J Immunol 2013; 191: 2001-2008.
57. Curiel TJ, Cheng P, Mottram P, et al. Dendritic cell subsets differentially regulate angiogenesis in human ovarian cancer. Cancer Res 2004; 64: 5535-5538.
58. Inoshima N, Nakanishi Y, Minami T, et al. The influence of dendritic cell infiltration and vascular endothelial growth factor expression on the prognosis of non-small cell lung cancer. Clin Cancer Res 2002; 8: 3480-3486.

Address for correspondence

Olga Stasikowska-Kanicka MSc, PhD
Department of Nephropathology
Medical University of Lodz
Czechoslowacka 8/10
92-216 Lodz, Poland
tel./fax +48 42 679 01 91
e-mail: olga.stasikowska@umed.lodz.pl
Copyright: © 2017 Polish Association of Pathologists and the Polish Branch of the International Academy of Pathology This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
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