Hyperglycemia Impairs Neutrophil Mobilization Leading to Enhanced Metastatic Seeding

Introduction:

Cancer is a devastating disease where a large proportion of patients succumb to metastatic spread of the disease to distant organs. Diabetes patients are at an increased risk of being diagnosed with cancer and face poorer prognosis mainly due to increased metastatic spread. With diabetes rates continuously rising, understanding why cancer patients with underlying diabetes are more susceptible to develop metastatic disease is of upmost importance. In previous studies, we have shown that neutrophils have the capacity to limit metastatic seeding. This knowledge, together with reports suggesting that neutrophil function is impaired in hyperglycemia, prompted us to test whether increased metastatic spread in diabetes is a result of hyperglycemia-induced neutrophil dysfunction.

Materials and method:

To this end we evaluated tumor growth and metastatic progression of 4T1 mammary tumor cells in Streptozotocin-induced hyperglycemic mice.

Results and discussion:

Our data show that while primary tumor growth is attenuated in hyperglycemia, metastatic progression is enhanced. Surprisingly, although neutrophil mobilization is impaired in hyperglycemic tumor bearing mice, neutrophil function remains intact. We find that reduced neutrophil mobilization in hyperglycemic mice during the premetastatic stage is due to reduced G-CSF secretion and results in an increase in metastatic seeding. Finally, our data show that while normalizing glucose levels rescues primary tumor growth, it concomitantly restores neutrophil mobilization and reduces metastatic seeding in the lungs.

Conclusion:

Taken together, our results show that impaired neutrophil mobilization in hyperglycemic tumor bearing mice leads to an increase in metastatic seeding and therefore to a worse outcome. Our work presents novel insights into the deleterious effect of hyperglycemia on immune function and how this affects tumor growth and metastatic progression. Our work further demonstrates the critical importance managing blood glucose levels and has significant implications for cancer patients with underlying diabetes.