Neural regulation of cancer: from mechanobiology to inflammation

Abstract

Despite recent progress in cancer research, the exact nature of malignant transformation and its progression is still not fully understood. Particularly metastasis, which accounts for most cancer death, is a very complex process, and new treatment strategies require a more comprehensive understanding of underlying regulatory mechanisms. Recently, the sympathetic nervous system (SNS) has been implicated in cancer progression and beta-blockers have been identified as a novel strategy to limit metastasis. This review discusses evidence that SNS signaling regulates metastasis by modulating the physical characteristics of tumor cells, tumor-associated immune cells and the extracellular matrix (ECM). Altered mechanotype is an emerging hallmark of cancer cells that is linked to invasive phenotype and treatment resistance. Mechanotype also influences crosstalk between tumor cells and their environment, and may thus have a critical role in cancer progression. First, we discuss how neural signaling regulates metastasis and how SNS signaling regulates both biochemical and mechanical properties of tumor cells, immune cells and the ECM. We then review our current knowledge of the mechanobiology of cancer with a focus on metastasis. Next, we discuss links between SNS activity and tumor-associated inflammation, the mechanical properties of immune cells, and how the physical properties of the ECM regulate cancer and metastasis. Finally, we discuss the potential for clinical translation of our knowledge of cancer mechanobiology to improve diagnosis and treatment.

Perioperative biobehavioral interventions to prevent cancer recurrence through combined inhibition of β‐adrenergic and cyclooxygenase 2 signaling

“…78 Platelet activity is known to be influenced by COX1 activation, and emerging evidence suggests that platelets are involved in various prometastatic processes, including the suppression of NK cell cytotoxicity, the secretion of growth factors, the shielding of tumor cells, and the facilitation of tumor migration and invasion. PGs cause immune and tumor cells to secrete MMP2 and MMP9; this leads to extracellular matrix degradation, which facilitates tumor cell extravasation.…”

“…12,16,17,43 Adrenergic signaling increases the numbers of monocytes in the circulation 54 and stimulates tumor cells to secrete chemokines (eg, colony stimulating factor 1 [CSF1] and C-C motif chemokine ligand 2 [CCL2]), which attract monocytes to infiltrate the tumor and evolve into macrophages. 58,78 Within this tumor microenvironment, β2-adrenergic signaling polarizes macrophages to acquire M2-like characteristics and to suppress M1-like characteristics 79 and thereby transforms them into cancer-promoting tumor-associated macrophages, and PGs have been shown to enhance this polarization through the CREB-KLF4 pathway. 80 Importantly, macrophages that exhibit M2like characteristics have been shown to suppress cellmediated immunity and promote tumor extravasation and metastasis 79 ; they have a pertinent role in tumor progression, especially in its early stages.…”

“…PGs cause immune and tumor cells to secrete MMP2 and MMP9; this leads to extracellular matrix degradation, which facilitates tumor cell extravasation. 78 Platelet activity is known to be influenced by COX1 activation, and emerging evidence suggests that platelets are involved in various prometastatic processes, including the suppression of NK cell cytotoxicity, the secretion of growth factors, the shielding of tumor cells, and the facilitation of tumor migration and invasion. 87 Furthermore, chronic stress and specifically sympathetic activation were shown to increase lymphatic vascular density and lymphatic flow in various animal models (and also lymphatic flow in humans).…”

Recent advances in understanding the complexities of metastasis

“…It is a multifaceted and complex series of events 7 , which is influenced at all stages by the intrinsic cellular mutational burden and the numerous bidirectional interactions between malignant and non-malignant cell types and is continuously fine-tuned by the various extrinsic microenvironmental niches, including the biochemistry and biomechanics of the extracellular matrix (ECM) 8, 9 , and availability and activity of growth factors. This process continually evolves depending on the local and distal microenvironments that tumour cells find themselves within or transiting through 8, 10, 11 ( Figure 1) and is tuned by inflammation, angiogenesis, lymphangiogenesis, neoneurogenesis 12– 14 , and systemic physiologic stress-responsive pathways such as the sympathetic nervous system 15, 16 . Finally, tumour cells have been known for decades to have the capacity to fuse with one another, leading to further genetic instability, although how this fusion of tumour cells drives the biology of cancer is not yet clear 17– 19 .…”

CTI special feature on inflammatory diseases: a translational perspective

“…In fact, the sympathetic nervous system (SNS) has been implicated in cancer progression and blockade of these adrenoceptors have been identified as a novel strategy to limit metastasis. Kim et al 3 describe how neural signaling regulates metastasis and how SNS signaling regulates both biochemical and mechanical properties of tumour cells, tumour‐associated immune cells and inflammation. Altered mechanotype is an emerging hallmark of cancer cells that is linked to invasive phenotype and treatment resistance.…”