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The spectrum of resistance in SR/CR mice: the critical role of chemoattraction in the cancer/leukocyte interaction.

Riedlinger G, Adams J, Stehle JR, Blanks MJ, Sanders AM, Hicks AM, Willingham MC, Cui Z - BMC Cancer (2010)

Bottom Line: The ability of these transplantable cancer cell lines to induce leukocyte infiltration was quantified and the percentage of different populations of responding immune cells was determined using flow cytometry.We found that some cancer cells could escape from SR/CR resistance because they did not induce infiltration of SR/CR leukocytes.However, if infiltration of leukocytes was induced by co-injection with chemotactic factors, these same cancer cells could be effectively recognized and killed by SR/CR leukocytes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, North Carolina, 27157, USA.

ABSTRACT

Background: Spontaneous regression/complete resistance (SR/CR) mice are a unique colony of mice that possess an inheritable, natural cancer resistance mediated primarily by innate cellular immunity. This resistance is effective against sarcoma 180 (S180) at exceptionally high doses and these mice remain healthy.

Methods: In this study, we challenged SR/CR mice with additional lethal transplantable mouse cancer cell lines to determine their resistance spectrum. The ability of these transplantable cancer cell lines to induce leukocyte infiltration was quantified and the percentage of different populations of responding immune cells was determined using flow cytometry.

Results: In comparison to wild type (WT) mice, SR/CR mice showed significantly higher resistance to all cancer cell lines tested. However, SR/CR mice were more sensitive to MethA sarcoma (MethA), B16 melanoma (B16), LL/2 lung carcinoma (LL/2) and J774 lymphoma (J774) than to sarcoma 180 (S180) and EL-4 lymphoma (EL-4). Further mechanistic studies revealed that this lower resistance to MethA and LL/2 was due to the inability of these cancer cells to attract SR/CR leukocytes, leading to tumor cell escape from resistance mechanism. This escape mechanism was overcome by co-injection with S180, which could attract SR/CR leukocytes allowing the mice to resist higher doses of MethA and LL/2. S180-induced cell-free ascites fluid (CFAF) co-injection recapitulated the results obtained with live S180 cells, suggesting that this chemoattraction by cancer cells is mediated by diffusible molecules. We also tested for the first time whether SR/CR mice were able to resist additional cancer cell lines prior to S180 exposure. We found that SR/CR mice had an innate resistance against EL-4 and J774.

Conclusions: Our results suggest that the cancer resistance in SR/CR mice is based on at least two separate processes: leukocyte migration/infiltration to the site of cancer cells and recognition of common surface properties on cancer cells. The infiltration of SR/CR leukocytes was based on both the innate ability of leukocytes to respond to chemotactic signals produced by cancer cells and on whether cancer cells produced these chemotactic signals. We found that some cancer cells could escape from SR/CR resistance because they did not induce infiltration of SR/CR leukocytes. However, if infiltration of leukocytes was induced by co-injection with chemotactic factors, these same cancer cells could be effectively recognized and killed by SR/CR leukocytes.

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SR/CR leukocyte migration and cancer destruction. A proposed model for SR/CR mediated cancer cell killing. S180 secretes chemotactic factors that attract SR/CR leukocytes (SR) to the site of the cancer, allowing tight contact between the leukocytes and cancer cells to be made which facilitates tumor destruction. LL/2 and MethA produce little or no chemoattractant and are, therefore, not efficiently killed by SR/CR leukocytes. Co-injection of MethA or LL/2 with S180 results in attraction of SR/CR leukocytes to the site of the cancer and efficient cell killing of these cancer cell lines. This suggests that some cancer cells may escape from SR/CR resistance because they do not induce SR/CR leukocyte infiltration and demonstrates the importance of leukocyte infiltration in the SR/CR resistance mechanism.
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Figure 6: SR/CR leukocyte migration and cancer destruction. A proposed model for SR/CR mediated cancer cell killing. S180 secretes chemotactic factors that attract SR/CR leukocytes (SR) to the site of the cancer, allowing tight contact between the leukocytes and cancer cells to be made which facilitates tumor destruction. LL/2 and MethA produce little or no chemoattractant and are, therefore, not efficiently killed by SR/CR leukocytes. Co-injection of MethA or LL/2 with S180 results in attraction of SR/CR leukocytes to the site of the cancer and efficient cell killing of these cancer cell lines. This suggests that some cancer cells may escape from SR/CR resistance because they do not induce SR/CR leukocyte infiltration and demonstrates the importance of leukocyte infiltration in the SR/CR resistance mechanism.

Mentions: Although the outcome of the co-injection experiment with S180 and CFAF was somewhat unexpected, the results, coupled with our previous work demonstrating that S180, MethA, and LL/2 were killed in an in vitro assay [2], suggest that the ability to induce leukocyte infiltration may be the most significant factor between these cancer cells in their ability to be resisted by SR/CR mice. There appear to be common surface properties that allow a variety of cancer cells to be recognized, bound, and destroyed by SR/CR leukocytes when they are in close proximity (Figure 6). Our results demonstrate that S180 only enhances resistance against LL/2 locally in SR/CR mice and argues that the ability of S180 to induce leukocyte infiltration is the critical event in augmenting resistance. While immune infiltration is clearly important for the eradication of cell lines such as LL/2 and MethA, we cannot completely exclude the possibility that co-injection with S180 or CFAF also activates the effector mechanism of SR/CR leukocytes, in addition to the induction of their infiltration.


The spectrum of resistance in SR/CR mice: the critical role of chemoattraction in the cancer/leukocyte interaction.

Riedlinger G, Adams J, Stehle JR, Blanks MJ, Sanders AM, Hicks AM, Willingham MC, Cui Z - BMC Cancer (2010)

SR/CR leukocyte migration and cancer destruction. A proposed model for SR/CR mediated cancer cell killing. S180 secretes chemotactic factors that attract SR/CR leukocytes (SR) to the site of the cancer, allowing tight contact between the leukocytes and cancer cells to be made which facilitates tumor destruction. LL/2 and MethA produce little or no chemoattractant and are, therefore, not efficiently killed by SR/CR leukocytes. Co-injection of MethA or LL/2 with S180 results in attraction of SR/CR leukocytes to the site of the cancer and efficient cell killing of these cancer cell lines. This suggests that some cancer cells may escape from SR/CR resistance because they do not induce SR/CR leukocyte infiltration and demonstrates the importance of leukocyte infiltration in the SR/CR resistance mechanism.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2875217&req=5

Figure 6: SR/CR leukocyte migration and cancer destruction. A proposed model for SR/CR mediated cancer cell killing. S180 secretes chemotactic factors that attract SR/CR leukocytes (SR) to the site of the cancer, allowing tight contact between the leukocytes and cancer cells to be made which facilitates tumor destruction. LL/2 and MethA produce little or no chemoattractant and are, therefore, not efficiently killed by SR/CR leukocytes. Co-injection of MethA or LL/2 with S180 results in attraction of SR/CR leukocytes to the site of the cancer and efficient cell killing of these cancer cell lines. This suggests that some cancer cells may escape from SR/CR resistance because they do not induce SR/CR leukocyte infiltration and demonstrates the importance of leukocyte infiltration in the SR/CR resistance mechanism.
Mentions: Although the outcome of the co-injection experiment with S180 and CFAF was somewhat unexpected, the results, coupled with our previous work demonstrating that S180, MethA, and LL/2 were killed in an in vitro assay [2], suggest that the ability to induce leukocyte infiltration may be the most significant factor between these cancer cells in their ability to be resisted by SR/CR mice. There appear to be common surface properties that allow a variety of cancer cells to be recognized, bound, and destroyed by SR/CR leukocytes when they are in close proximity (Figure 6). Our results demonstrate that S180 only enhances resistance against LL/2 locally in SR/CR mice and argues that the ability of S180 to induce leukocyte infiltration is the critical event in augmenting resistance. While immune infiltration is clearly important for the eradication of cell lines such as LL/2 and MethA, we cannot completely exclude the possibility that co-injection with S180 or CFAF also activates the effector mechanism of SR/CR leukocytes, in addition to the induction of their infiltration.

Bottom Line: The ability of these transplantable cancer cell lines to induce leukocyte infiltration was quantified and the percentage of different populations of responding immune cells was determined using flow cytometry.We found that some cancer cells could escape from SR/CR resistance because they did not induce infiltration of SR/CR leukocytes.However, if infiltration of leukocytes was induced by co-injection with chemotactic factors, these same cancer cells could be effectively recognized and killed by SR/CR leukocytes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, North Carolina, 27157, USA.

ABSTRACT

Background: Spontaneous regression/complete resistance (SR/CR) mice are a unique colony of mice that possess an inheritable, natural cancer resistance mediated primarily by innate cellular immunity. This resistance is effective against sarcoma 180 (S180) at exceptionally high doses and these mice remain healthy.

Methods: In this study, we challenged SR/CR mice with additional lethal transplantable mouse cancer cell lines to determine their resistance spectrum. The ability of these transplantable cancer cell lines to induce leukocyte infiltration was quantified and the percentage of different populations of responding immune cells was determined using flow cytometry.

Results: In comparison to wild type (WT) mice, SR/CR mice showed significantly higher resistance to all cancer cell lines tested. However, SR/CR mice were more sensitive to MethA sarcoma (MethA), B16 melanoma (B16), LL/2 lung carcinoma (LL/2) and J774 lymphoma (J774) than to sarcoma 180 (S180) and EL-4 lymphoma (EL-4). Further mechanistic studies revealed that this lower resistance to MethA and LL/2 was due to the inability of these cancer cells to attract SR/CR leukocytes, leading to tumor cell escape from resistance mechanism. This escape mechanism was overcome by co-injection with S180, which could attract SR/CR leukocytes allowing the mice to resist higher doses of MethA and LL/2. S180-induced cell-free ascites fluid (CFAF) co-injection recapitulated the results obtained with live S180 cells, suggesting that this chemoattraction by cancer cells is mediated by diffusible molecules. We also tested for the first time whether SR/CR mice were able to resist additional cancer cell lines prior to S180 exposure. We found that SR/CR mice had an innate resistance against EL-4 and J774.

Conclusions: Our results suggest that the cancer resistance in SR/CR mice is based on at least two separate processes: leukocyte migration/infiltration to the site of cancer cells and recognition of common surface properties on cancer cells. The infiltration of SR/CR leukocytes was based on both the innate ability of leukocytes to respond to chemotactic signals produced by cancer cells and on whether cancer cells produced these chemotactic signals. We found that some cancer cells could escape from SR/CR resistance because they did not induce infiltration of SR/CR leukocytes. However, if infiltration of leukocytes was induced by co-injection with chemotactic factors, these same cancer cells could be effectively recognized and killed by SR/CR leukocytes.

Show MeSH
Related in: MedlinePlus