Immune predictors of cancer progression

Toh, Benjamin; Chew, Valerie; Dai, Xilei; Khoo, Karen; Tham, Muly; Wai, Lu-En; Hubert, Sandra; Velumani, Sumathy; Zhi, Liang; Huang, Caleb; Abastado, Jean-Pierre

doi:10.1007/s12026-012-8288-4

Cited by 8 publications

(8 citation statements)

References 22 publications

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“…not significant. natural killer cells and macrophages can affect tumor growth 39,[46][47][48] . We can use the proposed model to study the role of the immune system in tumor development.…”

Section: Discussionmentioning

confidence: 99%

Development and characterization of mammary intraductal (MIND) spontaneous metastasis models for triple-negative breast cancer in syngeneic mice

Luo

Lin

et al. 2020

Sci Rep

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triple-negative breast cancer (tnBc) has a more aggressive phenotype and higher metastasis and recurrence rates than other breast cancer subtypes. tnBc currently lacks a transplantation model that is suitable for clinical simulations of the tumor microenvironment. intraductal injection of tumor cells into the mammary duct could mimic the occurrence and development of breast cancer. Herein, we injected 4T1 cells into the mammary ducts of BALB/C mice to build a preclinical model of tnBc and optimized the related construction method to observe the occurrence and spontaneous metastasis of tumors. We compared the effects of different cell numbers on tumorigenesis rates, times to tumorigenesis, and metastases to determine the optimal number of cells for modelling. We demonstrated that 4T1-MIND model mice injected with 20,000 cells revealed a suitable tumor formation rate and time, thus indicating a potential treatment time window after distant metastasis. We also injected 20,000 cells directly into the breast fat pad or breast duct for parallel comparison. The results still showed that the 4T1-MIND model provides sufficient treatment time for lung metastases in mice and that it is a more reliable model for early tumor development. The 4T1-MIND model requires continuous improvement and optimization. A suitable and optimized model for translational research and studies on the microenvironment in tnBc should be developed.Breast cancer is the most commonly diagnosed cancer type and the leading cause of cancer death among women worldwide 1,2 . Breast ductal carcinoma in situ (DCIS) accounts for 15%-30% of all breast cancer cases 3 . DCIS tends to break through the matrix and develop into invasive ductal carcinoma 4 . Approximately 90% of all breast cancer-related deaths are caused by metastasis 5,6 , the most frequent sites of which are the lung, bone, liver, and brain. Triple-negative breast cancer (TNBC) is remarkably heterogeneous in terms of the tumor microenvironment 7 . Preclinical models that can return the breast tumor microenvironment to its original condition play a pivotal role in studies on the pathogenesis and treatment of breast cancer. However, 23 anticancer drugs failed in clinical trials between 2007 and 2010 8 , partly because the preclinical models used to test them were inappropriate for breast cancer. These findings illustrate that the success of breast cancer research and treatment depends on the experimental animal model used.Experimental animal models of breast cancer have been widely studied. Researchers should choose different animal models based on the needs of their experimental work. Today, the most frequently used breast cancer models include spontaneous breast cancer animal models 9-11 , induced breast cancer animal models 11-15 , allograft experimental animal mammary cancer models [16][17][18][19] , xenograft breast cancer models 20-24 , distant metastasis of breast cancer models 17,25-27 and genetically engineered mouse models (GEMMs) of breast cancer [28][29][30] . Given the Pathological fe...

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“…not significant. natural killer cells and macrophages can affect tumor growth 39,[46][47][48] . We can use the proposed model to study the role of the immune system in tumor development.…”

Section: Discussionmentioning

confidence: 99%

Development and characterization of mammary intraductal (MIND) spontaneous metastasis models for triple-negative breast cancer in syngeneic mice

Luo

Lin

et al. 2020

Sci Rep

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“…This is likely due to the intact immune system of the BALB/cJ mice, rejecting the tumor cells or to the cells being insufficient in number to re-model the local extracellular matrix. It has been known for many years that lymphocytes can affect tumor growth [19] and it has been found that natural killer cells, tumor-associated macrophages (TAMs), T-regulatory (Treg) and dendritic cells play a role in tumorigenesis [20]–[22]. Further, stimulation of all of these immune cell types has been shown in response to tumor implantation in BALB/cJ mice, those used in our model [23]–[25].…”

Section: Discussionmentioning

confidence: 99%

Development and Characterization of a Preclinical Model of Breast Cancer Lung Micrometastatic to Macrometastatic Progression

et al. 2014

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Most cancer patients die with metastatic disease, thus, good models that recapitulate the natural process of metastasis including a dormancy period with micrometastatic cells would be beneficial in developing treatment strategies. Herein we report a model of natural metastasis that balances time to complete experiments with a reasonable dormancy period, which can be used to better study metastatic progression. The basis for the model is a 4T1 triple negative syngeneic breast cancer model without resection of the primary tumor. A cell titration from 500 to 15,000 GFP tagged 4T1 cells implanted into fat pad number four of immune proficient eight week female BALB/cJ mice optimized speed of the model while possessing metastatic processes including dormancy and beginning of reactivation. The frequency of primary tumors was less than 50% in animals implanted with 500–1500 cells. Although implantation with over 10,000 cells resulted in 100% primary tumor development, the tumors and macrometastases formed were highly aggressive, lacked dormancy, and offered no opportunity for treatment. Implantation of 7,500 cells resulted in >90% tumor take by 10 days; in 30–60 micrometastases in the lung (with many animals also having 2–30 brain micrometastases) two weeks post-implantation, with the first small macrometastases present at five weeks; many animals displaying macrometastases at five weeks and animals becoming moribund by six weeks post-implantation. Using the optimum of 7,500 cells the efficacy of a chemotherapeutic agent for breast cancer, doxorubicin, given at its maximal tolerated dose (MTD; 1 mg/kg weekly) was tested for an effect on metastasis. Doxorubicin treatment significantly reduced primary tumor growth and lung micrometastases but the number of macrometastases at experiment end was not significantly affected. This model should prove useful for development of drugs to target metastasis and to study the biology of metastasis.

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“…While the infiltration of effector lymphocytesisgenerally associated with a good prognosis, the infiltration of other immune cell populations (i.e.Myeloid Derived Suppressor Cells (MDSC) and T regulatory cells (Treg)) isthought to promote tumor progression by restraining tumor immunity and promoting neoplastic cell invasion and metastasis [1]. The identification of FOXP3, CD25 and CD4 as Treg associated markers prompted the investigation of the presence of this population in the immune infiltrate as a prognostic marker in various human malignancies [2].…”

Section: Introductionmentioning

confidence: 99%

FOXP3 Subcellular Localization Predicts Recurrence in Oral Squamous Cell Carcinoma

Weed

Walker²,

Fuente³

et al. 2013

PLoS ONE

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Forkhead box protein P3 (FOXP3) expression in tumor infiltrating CD4+T cells is generally associated with an intrinsic capacity to suppress tumor immunity. Based on this notion, different studies have evaluated the prognostic value of this maker in cancer but contradictory results have been found. Indeed, even within the same cancer population, the presence of CD4+FOXP3+T cells has been associated,with either a poor or a good prognosis, or no correlation has beenfound. Here, we demonstrate,in patients with oral squamous cell carcinoma (OSCC), that what really represents a prognostic parameter is not the overall expression of FOXP3 but its intracellular localization.While overallFOXP3 expression in tumor infiltrating CD4+T cells does not correlate with tumor recurrence, its intracellular localization within the CD4 cells does: nuclear FOXP3 (nFOXP3) is associated with tumor recurrence within 3 years, while cytoplasmicFOXP3 (cFOXP3) is associated with a lower likelihood of recurrence. Thus, we propose elevated levels of the cFOXP3/nFOXP3 ratio within tumor infiltrating CD4+ T cells as a predictor of OSCC recurrence.

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Immune predictors of cancer progression

Cited by 8 publications

References 22 publications

Development and characterization of mammary intraductal (MIND) spontaneous metastasis models for triple-negative breast cancer in syngeneic mice

Development and characterization of mammary intraductal (MIND) spontaneous metastasis models for triple-negative breast cancer in syngeneic mice

Development and Characterization of a Preclinical Model of Breast Cancer Lung Micrometastatic to Macrometastatic Progression

FOXP3 Subcellular Localization Predicts Recurrence in Oral Squamous Cell Carcinoma

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