Proliferative response of human and animal tumours to surgical wounding of normal tissues: onset, duration and inhibition

Abstract

Summary Acceleration of secondary tumour growth and metastases following excision of a primary tumour has been attributed to the consequent removal of primary tumour-generated inhibitory factors. However, our studies have shown that surgical wounding of normal tissues significantly stimulated the growth of malignant tissues without the concomitant presence or excision of a tumour mass. A humoral stimulating component was indicated by the proliferative response of tumours and metastases distant from the surgical wound. All 16 human and murine tumours, of nine different histologies, showed a measurable acceleration of growth when implanted in surgically treated animals, suggesting that the ability of malignant tissue to respond to surgical wounding of normal tissue was not histologically or species specific. The proliferative surge of malignant tissues was detectable soon after wounding and had a duration of 2-3 days. The surgical wound as the source of the tumour-stimulating factor(s) was affirmed by the significant inhibition of tumour proliferative responses when a somatostatin analogue was applied topically to the surgical wound within 1 h of wounding, and/or during the critical tumour-stimulatory period of 1-2 days after wounding. A potential therapeutic window for reducing a risk factor that may be inadvertently imposed upon every surgical/oncology patient is indicated.Keywords: surgical wounding; wound-generated tumour growth factor; tumour proliferative response; lanreotide; normal tissue trauma Inhibition of tumour growth by tumour mass is a phenomenon recognized and repeatedly studied since the early 1900s (Ehrlich, 1908;Marie and Clunet, 1910;Tyzzer, 1913). Numerous reports, summarized more recently by Keller (1983) and O'Reilly et al (1994), have indicated that the presence of a primary tumour inhibits the growth rate of metastases or of a second tumour implant, and that removal or eradication of the primary tumour accelerates growth at secondary sites. Early explanations for apparent exacerbations of disease reflected Ehrlich's hypothesis of 'Athrepsia'; that any actively growing tumour removed certain specific nutritive material necessary for growth from the host animal (Ehrlich and Apolant, 1905). Subsequent explanations stressed surgical relief from growth-limiting factors, such as anatomical boundaries, anoxia and nutritional deficiencies, or that the immunological relation between host and tumour was somehow altered by surgery, thereby facilitating tumour escape. However, the underlying cause of the occasional explosive metastatic manifestation after resection of 'primary' malignancy remained in question. An alternative explanation, proposed by Keller (1983) inhibitor (angiostatin). They postulated that a primary tumour, while capable of stimulating angiogenesis in its own vascular bed by generating angiogenic stimulators in excess of angiogenesis inhibitors, the angiogenesis inhibitor, by virtue of its longer halflife in the circulation, reaches the vascular bed of a secondary tumour in excess o...

Postoperative wound complications and systemic recurrence in breast cancer

“…Various other mechanisms explain how other factors like VEGF, PDGF and interleukins influence tumour growth (Dvorak, 1986;Dvorak et al, 1995;Abramovich et al, 1999;Balkwill and Mantovani, 2001;Coussens and Werb, 2002;Chang et al, 2005). There is also evidence to suggest that cell-mediated immunity and natural killer cell function is suppressed by the effect of anaesthesia and the post-surgical stress response (Bogden et al, 1997). If this 'window period' of decreased immunity is prolonged by wound complications like flap necrosis and breakdown, there may be increased growth of occult micro metastases.…”

TNF-α increases human melanoma cell invasion and migration in vitro: the role of proteolytic enzymes

“…To investigate this, animal studies have been undertaken which suggested that mediators released locally in the wound and systemically during the inflammatory phases of wound healing promote the growth, invasion and metastatic potential of human melanoma and other malignant tumour xenografts (Bogden et al, 1997;Hofer et al, 1998). There is also evidence from our laboratory that melanoma invasion in a model of human reconstructed skin requires the presence of host skin cells (namely fibroblasts and keratinocytes) that express characteristics of 'wounded' skin (Eves et al, 2000;Eves et al, in press).…”

NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells

“…Acceleration of cancer progression after surgery is evident in clinical settings and in experimental animals (Kodama et al, 1992;Bogden et al, 1997). This means that tissue injury accompanying surgical treatment may offer the specific environment which influences dissemination of cancer cells, if residual cancer cells are present in the resected margin or in the wound fluid.…”

“…Since surgical resection of carcinomas often results in acceleration of cancer progression and dissemination (Kodama et al, 1992;Bogden et al, 1997), we considered that HGF might influence the invasive potential of pancreatic cancers after surgery. To address this issue, SUIT-2 cells were cultured in the Matrigel invasion chamber in the presence of ascites obtained from a surgical patient with pancreatic cancer ( Figure 6A).…”