Abstract
Breast cancer patients who initially respond to cancer therapies often succumb to distant recurrence of the disease. It is not clear why people with the same type of breast cancer respond to treatments differently; some escape from dormancy and relapse earlier than others. In addition, some tumor clones respond to immunotherapy while others do not. We investigated how autophagy plays a role in accelerating or delaying recurrence of neu-overexpressing mouse mammary carcinoma (MMC) following adriamycin (ADR) treatment, and in affecting response to immunotherapy. We explored two strategies: 1) transient blockade of autophagy with chloroquine (CQ), which blocks fusion of autophagosomes and lysosomes during ADR treatment, and 2) permanent inhibition of autophagy by a stable knockdown of ATG5 (ATG5KD), which inhibits the formation of autophagosomes in MMC during and after ADR treatment. We found that while CQ prolonged tumor dormancy, but that stable knockdown of autophagy resulted in early escape from dormancy and recurrence. Interestingly, ATG5KD MMC contained an increased frequency of ADR-induced polyploid-like cells and rendered MMC resistant to immunotherapy. On the other hand, a transient blockade of autophagy did not affect the sensitivity of MMC to immunotherapy. Our observations suggest that while chemotherapy-induced autophagy may facilitate tumor relapse, cell-intrinsic autophagy delays tumor relapse, in part, by inhibiting the formation of polyploid-like tumor dormancy.
Highlights
Autophagy plays a paradoxical role in the promotion and inhibition of cancer
In order to determine whether ADR induces autophagy and in turn establishes tumor dormancy, mammary carcinoma (MMC) cells were treated with ADR in the presence or absence of CQ, a pharmacological agent used to block the final stages of autophagy, the fusion of autophagosomes with lysosomes that is necessary for digestion of the cargo in the autophagosomes
We showed that the presence of CQ during ADR treatment, in vitro, resulted in prolonging tumor dormancy such that, while ADR treated MMC resumed cell proliferation 6 weeks after the treatment, ADR+CQ treated MMC remained dormant (Figure 2A)
Summary
Autophagy plays a paradoxical role in the promotion and inhibition of cancer. On the one hand, autophagy has a cancer-promoting role by protecting tumor cells from chemotherapy or providing a source of energy for tumor cells to survive under hypoxic and acidic conditions despite the lack of mature vessels [1].On the other hand, inhibition of autophagy by disruption of Beclin 1 or deletion of ATG5 increases the frequency of spontaneous malignancies [2] or liver tumor [3], respectively. There are three major types of autophagy which include micro-autophagy involving the direct engulfment of cytosolic material by lysosomes through invagination, chaperone-mediated autophagy involving HSP70 and the lysosomal membrane associated protein 2 A (LAMP2A), and macro-autophagy which is a highly conserved pathway involving the formation of autophagosomes, which fuse with lysosomes. To this end, ATG5 is involved in the elongation of autophagosomes to engulf toxic material for degradation. We performed a permanent inhibition of cell-intrinsic macro-autophagy by a stable knockdown of ATG5 in tumor cells. We demonstrated that cell-intrinsic, but not chemotherapyinduced, autophagy can inhibit tumor relapse
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