The Hypertensive Xenograft Model (HXM) ‐ A New Tool for Studying the Role of Hypertension in Cancer

It is extremely common for a cancer patient to have a comorbidity (i.e., co‐existing condition) that potentially impacts outcome. The most common comorbidity of cancer is cardiovascular disease (CVD), of which hypertension is the most prevalent. Although hypertension is the most frequent comorbidity of cancer patients and is frequently correlated with outcome, no experimental animal models of hypertensive cancer patients exist and the mechanisms that underlie the interactions between the two diseases are unknown. In other words, we have been studying cancer in animals who are otherwise completely healthy and this is perhaps less relevant to the actual patient population when compared with the novel hypertensive xenograft model (HXM) that we have developed for the experimental study of cancer in the context of hypertension. To generate a HXM strain, we used genome‐engineering to mutate IL2Rγ in the SS rat (SS IL2Rγ ), which is a very well characterized model of salt‐sensitive hypertension that has been studied for >50 years. Like conventional xenograft host strains, human cancer cells can be orthotopically inoculated into the SS IL2Rγ rat to assess cancer phenotypes. The salient difference between HXM and conventional xenograft models is the ability to induce hypertension in the SS IL2Rγ rat by merely elevating dietary salt from 0.25% NaCl to 4% NaCl, which enables cancer to be studied in the same inbred HXM strain under normotensive and hypertensive conditions. To differentiate hypertension from the effects that dietary salt might directly have on cancer, we have also generated a second IL2Rγ‐deficient strain on the resistant SD background (SD IL2Rγ ) that does not develop hypertension on the 4% NaCl diet. HXM utilizes engraftment of transgenically tagged human cancer cells with defined clinical properties. Thus, it enables testing of clinically relevant cancer models in the context of hypertension that are highly relevant to cancer patients. In this study, we used our new HXM rat strains to study the mechanistic role of hypertension in breast cancer for the first time. Tumor‐bearing SS IL2Rγ rats on 4% NaCl diet for 30 days had significantly elevated blood pressure (142 ± 1 mmHg; P <0.05) compared with 231 Luc+ tumor‐bearing SS IL2Rγ rats on 0.25% NaCl diet (122 ± 5 mmHg). The hypertensive SS IL2Rγ rats on the 4% NaCl diet had significantly decreased tumor growth (35%; P <0.05) and metastasis (>99%; P <0.05) compared with the normotensive SS IL2Rγ rats on the 0.25% NaCl diet. We also found that the 231 Luc+ tumors implanted in the hypertensive SS IL2Rγ rats had a ~50% ( P <0.05) reduction in tumor blood vessels compared with the normotensive SS IL2Rγ rats, indicating that hypertension‐induced vascular dysfunction in the tumor microenvironment might affect tumor progression. Collectively, the novel mechanistic data generated by the HXM strategy will provide the first mechanistic insight to the widely associated, yet poorly understood interactions between hypertension and cancer. Support or Funding Information NIH (R01CA193343);Mary Kay Foundation (Grant No. 024.16); Wisconsin Breast Cancer Showhouse