Date of Award
Summer 8-15-2018
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
The tumor microenvironment plays a pivotal role in tumor progression, and there is mounting evidence for synergistic action between tumor cells and microenvironmental cells that help the former thrive and even metastasize to other organs. This dissertation is focused on investigating the potential of therapeutically targeting the microenvironment to reduce breast cancer metastases and chemotherapy-induced bone loss. In Chapter 2 we investigate the efficacy of p38MAPK/MK2 inhibitors in limiting breast cancer metastasis by targeting the stromal compartment. Chapter 3 is centered around identification of mechanisms that drive chemotherapy-induced bone loss and the potential role for chemotherapy-induced senescence in this bone loss.
Tumor-associated stromal cells are notorious for secreting factors that have pro-tumorigenic capabilities. The stress kinase, p38MAPK, is known to regulate the expression of several of these tumor-promoting stromal factors that in fact, have been found in the stroma of breast cancer patients. Moreover, p38MAPK_ is frequently upregulated in a variety of cancers including breast cancer, and its expression correlates with poor prognosis. In earlier work, we demonstrated that inhibition of p38MAPK resulted in attenuated primary tumor growth and this effect is through blocking secretion of stromal factors. This effect at the primary site, led us to investigate whether inhibition of p38MAPK_ could reduce breast cancer metastases in a clinically relevant model. In this dissertation, we show that orally administered, small-molecule inhibitors of p38MAPK_ and its downstream kinase, MK2, each limited outgrowth of metastatic breast cancer cells in the bone and visceral organs. We demonstrate that this effect is due to the inhibition of the p38MAPK_ pathway within the stromal compartment. In addition, these inhibitors effectively inhibited tumor-associated and chemotherapy-induced bone loss, which represent significant comorbidities for cancer patients. We show that targeting the stromal p38MAPK-MK2 pathway limits metastatic breast cancer growth while preserving bone quality and extending survival.
The second part of this dissertation focuses on investigating estrogen-independent mechanisms that drive bone loss following chemotherapy treatment. Patients who receive chemotherapy treatment experience significant loss in bone density. Chemotherapy is thought to lead to bone loss by inducing premature menopause, which subsequently results in estrogen loss. Given that estrogen plays an important role in bone homeostasis, the loss of ovarian function is thought to drive bone loss in women undergoing chemotherapy. While it is clear estrogen is important in bone homeostasis and its loss following chemotherapy contributes to bone loss, these observations do not fully explain why post-menopausal women, who have already undergone physiological ovarian failure, lose significant bone density following therapy. Further, therapy-induced bone loss is more rapid and severe than bone loss seen with aging or post-menopause. Together, these observations suggest that factors or mechanisms in addition to estrogen loss contribute to chemotherapy-induced bone loss. Given that chemotherapeutic agents robustly induce senescence in vitro and in vivo, we postulated that chemotherapy-induced senescence and SASP activation contributes to bone loss. We used a Doxorubicin-induced bone loss model in mice and observed that chemotherapy reduced bone volume significantly more than the classic OVX model of estrogen deficiency both in young (6-week old) and skeletally mature (16-week old) mice in C57BL/6 and FVB/NJ strains. To evaluate the role of senescence in chemotherapy-induced bone loss, we profiled the expression of several senescence-associated factors in bones devoid of marrow. We observed induction of senescence marker p16, and factors including IL-6 and Dkk1, in 6-week old mice at the early (48 hour post Doxorubicin) timepoint and 16-week old chemotherapy mice at the final (10 days post Doxorubicin) timepoint. However, the upregulation did not repeat in 16-week old mice, leaving some questions of inconsistencies that will be addressed in prospective studies. In line with our hypothesis, we treated mice with p38MAPK and MK2 inhibitors to block production of senescence-associated proresorptive factors and observed preservation of bone integrity in chemotherapy-treated mice. In conclusion, we established that there are estrogen-independent mechanisms involved in chemotherapy-induced bone loss. However, the contribution of senescence and the mechanism of bone preservation by p38i and MK2Pi requires further evaluation.
Overall, targeting the microenvironment with the intent of disrupting the stromal-tumoral collaboration may be a viable therapeutic strategy to combat tumor progression and related pathologies that result from cancer treatments.
Language
English (en)
Chair and Committee
Sheila A. Stewart
Committee Members
Daniel Link, Joshua Rubin, Deborah Veis, Katherine Weilbaecher,
Recommended Citation
Murali, Bhavna, "Targeting the Microenvironment: Approaches for Reducing Breast Cancer Metastases and Chemotherapy-induced Bone Loss" (2018). Arts & Sciences Electronic Theses and Dissertations. 1642.
https://openscholarship.wustl.edu/art_sci_etds/1642
Comments
Permanent URL: 2020-08-02