Surgery, Circulating Tumor Cells, and the Spread of Cancer
Questions from the Clinic:
Does surgical intervention increase or otherwise influence the number of circulating tumor cells in cancer patients and does that impact outcomes? Are there are any perioperative procedures or treatments that alter the activity of cancers and development of circulating tumor cells?
I. Historical Context
To achieve control of most solid cancers, clinicians frequently remain dependent on surgical resection. Although excision of primary tumors can save and extend lives, accumulating evidence indicates that the removal process may promote the metastatic seeding of cancer cells.(1) The link between tumor removal and recurrence has been known for much of the 20th century, but the mechanisms underlying this relationship took decades to elucidate fully.(2) Over time, investigators have directed their attention to circulating tumor cells, or CTCs, which travel to sites of physical or chemical injury.(3) Surgically-induced trauma can trigger a multifaceted, inflammatory response that promotes the migration and proliferation of CTCs.(2) Across multiple studies, researchers have noted that CTC counts rise after surgery for breast, colorectal, gastric, hepatocellular, and lung cancers.(4,5,6,7,8) Because postoperative disease recurrence locally and possibly distantly has a high risk of morbidity and mortality and occurs in upwards of a third of patients, it is arguably one of the greatest unresolved problems in modern medicine.(9)
II. Circulating Tumor Cells - Mechanism of Action
Surgical stress activates the sympathetic nervous system and several classes of immune cells that create conditions favorable for cancer growth. Elevated levels of epinephrine and norepinephrine results in the activation of β-adrenoceptors, which are upregulated on tumor cells. Once active, β-adrenoceptors initiate a cascade of intracellular signaling that culminates in the transcription of factors linked with metastasis, like HIFs, MMPs, and VEGF.9 Structurally, in response to these signals, tumor cells form actin-rich protrusions known as invadopodia.(10) Concurrently, flow through lymphatic vessels draining tumors increases in response to epinephrine and norepinephrine. This increased flow facilitates the dissemination of tumor cells in vivo, which are morphologically contractile and highly invasive.(11) The complement system, active during inflammation, further promotes cancer growth by enhancing the “stemness” or stem cell similarity of cancer cells, promoting angiogenesis, and reducing anti-tumor immunity.(1)