Increased extracellular pressure stimulates tumor proliferation by a mechanosensitive calcium channel and PKC‐β

Abstract

Large tumors exhibit high interstitial pressure heightened by growth against the constraining stroma. Such pressures could stimulate tumor proliferation via a mechanosensitive ion channel. We studied the effects of 0–80 mm Hg increased extracellular pressure for 24 hours on proliferation of SW620, Caco-2, and CT-26 colon; MCF-7 breast; and MLL and PC3 prostate cancer cells, and delineated its mechanism in SW620 cells with specific inhibitors and siRNA. Finally, we compared NF-kB, phospho-IkB and cyclin D1 immunoreactivity in the high pressure centers and low pressure peripheries of human tumors. Pressure stimulated proliferation in all cells. Pressure-driven SW620 proliferation required calcium influx via the T-type Ca2+ channel Cav3.3, which stimulated PKC-β to invoke the IKK-IkB-NF-kB pathway to increase proliferation and S-phase fraction. The mitotic index and immunoreactivity of NF-kB, phospho-IkB, and cyclin D1 in the center of 28 large human colon, lung, and head and neck tumors exceeded that in tumor peripheries. Extracellular pressure increases [Ca2+]i via Cav3.3, driving a PKC-β-IKK-IkB-NF-kB pathway that stimulates cancer cell proliferation. Rapid proliferation in large stiff tumors may increase intratumoral pressure, activating this pathway to stimulate further proliferation in a feedback cycle that potentiates tumor growth. Targeting this pathway may inhibit proliferation in large unresectable tumors.

Ion Channels in Cancer: Are Cancer Hallmarks Oncochannelopathies?

“…Cancer cells and ECs within an expanding tumor experience excessive compressive and shear forces due to increased extracellular matrix (ECM) stiffness and high interstitial pressure heightened by the growth against the constraining stroma. Such forces could stimulate proliferative, migratory, and invasive behaviors of cancer cells via a mechanosensitive ion channel in their plasma membrane (25) as well influence tumor angiogenesis (4). On the other hand, migratory and invasive behaviors requires generating mechanical force involving cytoskeletal and adhesion machinery in which mechanosensitive ion channels play the role of feedback sensors.…”

Primary breast cancer induces pulmonary vascular hyperpermeability and promotes metastasis via the VEGF–PKC pathway

“…In human airways, resident airway epithelial cells produce pro‐inflammatory mediators under the regulation of PKCδ, which increases NF‐κB‐dependent pro‐inflammatory cytokine generation. PKCα, PKCδ, and PKCϵ have reportedly been involved in the regulation of fibrosis in human pulmonary interstitial fibroblasts . PKC may play a critical role in mediating pulmonary inflammation diseases.…”

T-type Ca2+channels and autoregulation of local blood flow

“…41,54 However, a direct pressure-dependent activation of Ca 2C influx via VGCCs cannot play a major role in the myogenic response, since myogenic depolarization is dependent on opening of non-selective cation channels, 30,33 and is not affected by application of the L-type antagonist nifedipine. 114,115 The role of Ca V 3.1 channels (and perhaps Cav3.3 channels in human MCAs) in myogenic tone at lower pressures can be explained by a corresponding low myogenic depolarization in the range from approximately ¡65 to ¡50 mV, which activates a non-inactivation window-type Ca 2C current through these channels.…”

“…53 Application of 15 mmHg extracellular pressure to SW620 human cancer cells causes mechanical activation of Ca 2C influx through Ca V 3.3 T-type channels (but not through Ca V 3.1 or Ca V 3.2 channels), which activates PKC-b and stimulates proliferation of cancer cells. 54 There are no reports of direct mechano-sensitivity of Ca V 3.1 channels. Although not directly mechano-sensitive, the Ca V 3.2 T-type channels are important for normal excitability of skin D-hair receptors in mice.…”