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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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Naïve SR/CR pups resist the initial challenge with EL-4 and J774. Pups from an SR/CR × WT cross were challenged with 10e6 EL-4 prior to being challenged with any other cancer cell line and 22 out of 35 pups survived. Pups from an SR/CR × WT cross that were challenged with 5 × 10e5 and a second challenge with 5 × 10e6 S180 have a historical survival rate of ~30% [1,2]. When nine pups from an SR/CR × WT cross were challenged with 5 × 10e4 J774 prior to being challenged with any other cell line, one mouse survived. All WT mice challenged with EL-4, S180, and J774 at the indicated doses uniformly died. Mice were monitored for at least 60 days after challenge.
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Figure 2: Naïve SR/CR pups resist the initial challenge with EL-4 and J774. Pups from an SR/CR × WT cross were challenged with 10e6 EL-4 prior to being challenged with any other cancer cell line and 22 out of 35 pups survived. Pups from an SR/CR × WT cross that were challenged with 5 × 10e5 and a second challenge with 5 × 10e6 S180 have a historical survival rate of ~30% [1,2]. When nine pups from an SR/CR × WT cross were challenged with 5 × 10e4 J774 prior to being challenged with any other cell line, one mouse survived. All WT mice challenged with EL-4, S180, and J774 at the indicated doses uniformly died. Mice were monitored for at least 60 days after challenge.

Mentions: We injected naïve pups, age 6-8 weeks, with cancer cell lines other than S180 initially to determine if resistance to these cell lines was simply a result of cross-vaccination from antigens shared with S180 or if it was a result of innate recognition of a common surface property shared between different cancer cell lines. SR/CR mice had never previously been tested for their ability to resist additional cancer cell lines without first being able to survive challenge with S180. The naïve pups were obtained from our routine breeding scheme in which one C57BL/6 SR/CR parent is crossed with a C57BL/6 WT parent. In this breeding scheme, 30-40% of the naive pups were expected to survive the initial challenge with S180. Five weeks after the naïve pups were given 10e6 EL-4 as their first cancer challenge, 22 of 35 pups (65%) survived and remained apparently healthy (Figure 2). When naïve pups were first screened with J774 at 5 × 10e4, 1 of 9 pups survived.


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)

Naïve SR/CR pups resist the initial challenge with EL-4 and J774. Pups from an SR/CR × WT cross were challenged with 10e6 EL-4 prior to being challenged with any other cancer cell line and 22 out of 35 pups survived. Pups from an SR/CR × WT cross that were challenged with 5 × 10e5 and a second challenge with 5 × 10e6 S180 have a historical survival rate of ~30% [1,2]. When nine pups from an SR/CR × WT cross were challenged with 5 × 10e4 J774 prior to being challenged with any other cell line, one mouse survived. All WT mice challenged with EL-4, S180, and J774 at the indicated doses uniformly died. Mice were monitored for at least 60 days after challenge.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Naïve SR/CR pups resist the initial challenge with EL-4 and J774. Pups from an SR/CR × WT cross were challenged with 10e6 EL-4 prior to being challenged with any other cancer cell line and 22 out of 35 pups survived. Pups from an SR/CR × WT cross that were challenged with 5 × 10e5 and a second challenge with 5 × 10e6 S180 have a historical survival rate of ~30% [1,2]. When nine pups from an SR/CR × WT cross were challenged with 5 × 10e4 J774 prior to being challenged with any other cell line, one mouse survived. All WT mice challenged with EL-4, S180, and J774 at the indicated doses uniformly died. Mice were monitored for at least 60 days after challenge.
Mentions: We injected naïve pups, age 6-8 weeks, with cancer cell lines other than S180 initially to determine if resistance to these cell lines was simply a result of cross-vaccination from antigens shared with S180 or if it was a result of innate recognition of a common surface property shared between different cancer cell lines. SR/CR mice had never previously been tested for their ability to resist additional cancer cell lines without first being able to survive challenge with S180. The naïve pups were obtained from our routine breeding scheme in which one C57BL/6 SR/CR parent is crossed with a C57BL/6 WT parent. In this breeding scheme, 30-40% of the naive pups were expected to survive the initial challenge with S180. Five weeks after the naïve pups were given 10e6 EL-4 as their first cancer challenge, 22 of 35 pups (65%) survived and remained apparently healthy (Figure 2). When naïve pups were first screened with J774 at 5 × 10e4, 1 of 9 pups survived.

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