Abstract
Forces within the surgical milieu or circulation activate cancer cell adhesion and potentiate metastasis through signaling requiring FAK-Akt1 interaction. Impeding FAK-Akt1 interaction might inhibit perioperative tumor dissemination, facilitating curative cancer surgery without global FAK or AKT inhibitor toxicity. Serial truncation and structurally designed mutants of FAK identified a seven amino acid, short helical structure within FAK that effectively competes with Akt1-FAK interaction. Adenoviral overexpression of this FAK-derived peptide inhibited pressure-induced FAK phosphorylation and AKT-FAK coimmunoprecipitation in human SW620 colon cancer cells briefly exposed to 15mmHg increased pressure, consistent with laparoscopic or post-surgical pressures. Adenoviral FAK-derived peptide expression prevented pressure-activation of SW620 adhesion not only to collagen-I-coated plates but also to murine surgical wounds. A scrambled peptide did not. Finally, we modeled operative shedding of tumor cells before irrigation and closure by transient cancer cell adhesion to murine surgical wounds before irrigation and closure. Thirty minute preincubation of SW620 cells at 15mmHg increased pressure impaired subsequent tumor free survival in mice exposed to cells expressing the scrambled peptide. The FAK-derived sequence prevented this. These results suggest that blocking FAK-Akt1 interaction may prevent perioperative tumor dissemination and that analogs or mimics of this 7 amino acid FAK-derived peptide could impair metastasis.
Highlights
Disseminated tumor cells are pivotal in cancer metastasis
It is difficult to distinguish undetected preoperative metastases from metastases arising from tumor cells dislodged by surgical manipulation, 0.2-0.5% of potentially curative surgical resections are marred by surgical wound recurrence [6]
We have previously shown that FAK-Akt1 binding requires neither the FAK kinase nor focal adhesion targeting (FAT) domains; the highest Akt1 affinity depends on FERM domain residues 1-126 [30,31,32]
Summary
Disseminated tumor cells are pivotal in cancer metastasis. A one centimeter tumor sheds one million cells into the circulation daily [1]. Viable tumor cells [2] can frequently be recovered from the peritoneum [3] or portal or systemic circulation during colon cancer resections [4, 5]. It is difficult to distinguish undetected preoperative metastases from metastases arising from tumor cells dislodged by surgical manipulation, 0.2-0.5% of potentially curative surgical resections are marred by surgical wound recurrence [6]. Many more patients develop peritoneal dissemination or circulatory metastasis. Since most cancer patients die of metastasis, not primary tumors, inhibition of metastasis is highly desirable. Perioperative tumor dissemination can turn curative cancer resections into a metastatic fatalities
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
